When Translation Meets Metabolism: Multiple Links to Diabetes
Endocrine Research (Y.S., S.I.T.), Infectious Diseases (S.-L.T.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285; and Department of Biochemistry and McGill Cancer Center (N.S.), McGill University, Montréal, Quebéc H3G 1Y6, Canada&5.(]c;, 百拇医药
Abstract&5.(]c;, 百拇医药
Type 2 diabetes is a polygenic disorder characterized by multiple biochemical defects including transcriptional, translational, and posttranslational abnormalities. Although major progress has been made in elucidation of factors at the transcriptional and posttranslational levels, defects at the translational level remain elusive. Mutation of a kinase that regulates translation initiation has been implicated in the etiology of a monogenic form of diabetes known as Wolcott-Rallison syndrome. Characterization of mice rendered deficient in eukaryotic initiation factors has provided model systems to study the involvement of translation in regulating insulin synthesis and secretion, hepatic function, peripheral insulin resistance, and diabetic complications. Recent progress in the understanding of endoplasmic reticulum overload by unfolded proteins has begun to uncover mechanisms leading to pancreatic ß-cell exhaustion. Future advances in this area may lead to identification of the missing links in the pathogenesis of ß-cell failures due to conditions such as hyperinsulinemia, hyperglycemia, and long-term treatment with sulfonylureas, and thus may identify novel therapeutic targets for diabetes.
I. Introduction;ix, 百拇医药
II. The Unfolded Protein Response (UPR), Pancreatic eIF2{alpha} Kinase/PKR-Like ER-Kinase (PEK/PERK), and Diabetes;ix, 百拇医药
III. eIF2{alpha} Phosphorylation and Hepatic Glucose Output;ix, 百拇医药
IV. eIF4E Binding Protein and Insulin Sensitivity;ix, 百拇医药
V. S6K1 and Pancreatic ß-Cell Function;ix, 百拇医药
VI. Translational Control of CD36 Expression and Diabetes-Induced Atherosclerosis;ix, 百拇医药
VII. Conclusion and Prospects;ix, 百拇医药
I. Introduction;ix, 百拇医药
DIABETES IS A major epidemic that affects more than 5% of the US population (1). The most common form, type 2 diabetes, is a metabolic disease caused by defective insulin secretion and insulin resistance (2), whereas type 1 diabetes is an autoimmune disorder characterized by progressive destruction of insulin-producing islet ß-cells (3, 4). Insulin plays a pivotal role in regulating glucose homeostasis, and its synthesis and secretion are regulated at the transcriptional, translational, and posttranslational levels. The importance of transcriptional regulation has been underscored by recent progress in studying a rare form of human diabetes collectively known as maturity-onset diabetes of the young. Mutations in a number of transcription factors in the pancreatic ß-cells have been identified as the common causes of maturity-onset diabetes of the young (5, 6). However, insulin synthesis is acutely regulated primarily at the translational level (7, 8). For example, insulin synthesis in islet ß-cells is activated within minutes of glucose stimulation, whereas regulation at transcriptional levels occurs more slowly (9). Although diabetes resulting from mutations that cause translational defects is rare, recent work characterizing mice rendered deficient in regulators of translation initiation factor activity (10, 11, 12, 13) has shed new light on the possible involvement of translational control in diabetes.
The etiology of type 2 diabetes remains to be elucidated. A salient feature of type 2 diabetes is insulin resistance in skeletal muscle, liver, and adipose tissues (2). Insulin resistance presents a serious challenge to the islet ß-cell’s capacity for insulin synthesis and secretion. Normoglycemia can be maintained as long as the ß-cells can secrete enough insulin to compensate for the loss of insulin sensitivity. Such excess activity imposes stress on the islet ß-cells, which compromises the ability of the ß-cells to maintain normal functions such as glucose sensing, insulin synthesis, and secretion. Diabetes occurs when insulin secretion fails to compensate for insulin resistance (14, 15), as evidenced by the fact that almost all forms of diabetes involve ß-cell failure.w!6;/&, http://www.100md.com
A hallmark of the islet ß-cell is its capacity to synthesize and secrete large quantities of insulin. Under physiological conditions, more than 5% of the total protein content in ß-cells is insulin. This imposes on the ß-cell the requirement to be able to process and fold large amounts of secreted proteins. Hence, pancreatic ß-cells may be more vulnerable to stress conditions, such as accumulation of unfolded proteins and Ca2+ depletion in the endoplasmic reticulum (ER).
In this review, we describe recent progress in characterizing the role of ER stress and translational control in diabetes by focusing on the regulation of translation initiation in maintaining glucose homeostasis.:krn, 百拇医药
II. The Unfolded Protein Response (UPR), Pancreatic eIF2 Kinase/PKR-Like-ER-Kinase (PEK/PERK), and Diabetes:krn, 百拇医药
Islet ß-cells function as specialized secretory cells and are subjected to ER stress from accumulation of unfolded proteins and Ca2+ depletion. Secreted and membrane proteins are synthesized on ER-bound ribosomes and are translocated across the ER membrane to the lumenal environment where they undergo folding, proteolytic processing, posttranslational modification, and sorting. ER activity is controlled in part by regulating Ca2+ release in response to metabolic cues and cellular stimuli. In addition, the ER transmits signals to the cytoplasm and the nucleus, leading to either cellular adaptation for survival or induction of apoptosis. Thus, the ER may be particularly sensitive to environmental perturbations such as the accumulation of unfolded proteins and/or Ca2+ depletion (16).
Great strides have been made in the past few years in the understanding of the translational regulation of ER stress. Unfolded proteins in the ER are very toxic and pose a threat to the survival of the cell. Mammalian cells have evolved intricate mechanisms that respond to the accumulation of unfolded proteins, and these are collectively known as the UPR. The UPR functions to balance protein synthesis with the cell’s capacity for folding and processing proteins. The UPR reduces ER stress by up-regulating transcription of genes encoding ER chaperones and genes involved in the degradation of unfolded proteins, while simultaneously inhibiting general protein synthesis (16). This process is coordinated by two ER-associated type I transmembrane kinases: IRE1 (inositol requiring and ER-to-nucleus signaling) and PERK (Fig. 1). IRE1 was first identified in the yeast UPR and consists of three domains including a regulatory domain, a Ser/Thr kinase domain, and a ribonuclease L (RNaseL)-like domain (17). Accumulation of unfolded proteins in yeast results in activation of the RNaseL domain of Ire1p, which catalyzes the unusual mRNA splicing of the transcription factor Hac1p. Hac1p coordinately up-regulates a family of genes encoding protein chaperones (16, 18, 19). A mammalian homolog of HAC1 has recently been identified as Xbp-1 (X-box binding protein-1) (20, 21), a member of the cAMP regulatory element binding protein/activating transcription factor (CREB/ATF) family that is highly expressed in the exocrine gland (22).
fig.ommittedwk{67, http://www.100md.com
Figure 1. UPR mediated by IRE1 and PERK. Accumulation of unfolded proteins leads to activation of IRE1 and PERK by phosphorylation. IRE1 is a tripartite kinase that contains an ER regulatory domain (REG), a serine/threonine kinase domain, and an RNaseL domain (L). The small triangle indicates the IRE1-mediated productive splicing of yeast Hac1 mRNA and mammalian XBP-1 mRNA that coordinately activates a family of genes encoding ER chaperones. Binding of unfolded proteins to PERK leads to activation of its kinase domain, which phosphorylates eIF2, resulting in general inhibition of translation initiation.wk{67, http://www.100md.com
The second arm of the UPR involves activation of PEK/PERK, which phosphorylates eukaryotic initiation factor 2{alpha} (eIF2{alpha} ) (Fig. 1). PEK was first identified in pancreatic islets by expression cloning and was characterized as a novel eIF2{alpha} kinase (23). The kinase was named PEK (pancreatic eIF2{alpha} kinase) due to its abundant expression in pancreas (24). Independently, the same kinase was also identified as an ER-associated protein kinase that phosphorylates eIF2{alpha} kinase in response to ER stress and named PERK (PKR-like-ER-kinase) (25). PERK shares significant sequence homology with IRE1 in the N terminus that defines a lumenal domain. PERK is activated by phosphorylation of its kinase domain triggered by accumulation of unfolded proteins that are proposed to displace the heat shock protein-70-like ER chaperone, Bip, from binding to the lumenal domain (26). Phosphorylation of eIF2{alpha} by PERK leads to the inhibition of general protein synthesis but, remarkably, results in selective increase of mRNA translation of activating transcription factor 4 (ATF4), which regulates UPR (25, 27).
The physiological significance of PERK in regulating ER stress is underscored by genetic characterization of a familial disease known as Wolcott-Rallison syndrome (WRS). WRS is a rare autosomal recessive disorder characterized by diabetes mellitus, multiple epiphyseal dysplasia, osteoporosis, and growth retardation (28, 29). The disease causes islet ß-cell dystrophy without major detectable defect in the glucagon-secreting {alpha} -cells (30). WRS patients often die at a young age despite treatment with insulin. Chromosomal mapping and positional cloning have localized the WRS gene to chromosome 2p12, which contains the gene encoding PEK/PERK (31, 32). Sequence analysis of the PERK gene from WRS patients has identified two mutations that cause this recessive disorder (32).-.t(*15, http://www.100md.com
The role of PERK in maintaining the function of pancreatic ß-cells has been corroborated by recent studies on knockout mice lacking functional PERK (10). PERK knockout mice are born with an apparently normal phenotype, suggesting that PERK is not required for development. Reminiscent of the diabetic pathophysiology observed in patients with WRS, the knockout mice gradually develop diabetes between 2 and 4 wk of age. The onset of diabetes coincides with decreased levels of insulin mRNA and protein. In addition to defective islet ß-cells, PERK knockout mice develop abnormalities with glucagon-secreting {alpha} -cells and problems with exocrine pancreas (10, 13). PERK knockout mice also share other features in common with human WRS, such as growth retardation and multiple skeletal dysplasias (13).
The diabetic phenotype in PERK-/- mice is primarily caused by progressive loss of islet ß-cells, as evidenced by the high number of ß-cells that score positive for an apoptosis marker (10, 13). The extensive ß-cell death in PERK-/- islets appears to be caused by the accumulation of unfolded proteins in the ER, as suggested by abnormal ER morphology in PERK-/- cells (10). The ß-cell atrophy in the PERK-/- islet could be partially caused by increased activity of a parallel stress pathway mediated by IRE1 (Fig. 2), because overexpression of IRE1 has been shown to induce apoptosis mediated partly by activation of the Janus kinase pathway (33, 34). Elevation of the levels of transcription factor CHOP (C/EBP homologous protein) by ER stress may also contribute to the loss of islet ß-cells, as demonstrated in the Akita diabetic mouse (35). Hence, Akita mice deficient in CHOP showed resistance to apoptosis from nitric oxide treatment that depletes ER Ca2+ and causes ER-stress responses (35). Additionally, it is possible that hyperglycemia and defective ER Ca2+ homeostasis also contribute to apoptosis of pancreatic ß-cells in PERK-/- islets. In support of a role of hyperglycemia in causing ß-cell apoptosis, it has been observed that PERK induction by agents that cause ER stress is more pronounced in the presence of high glucose in the media (10). Hyperglycemia has been implicated as one cause of ß-cell apoptosis in animal models of diabetes (36, 37). Exposure of ß-cells from ob/ob mice and Wistar rats to high levels of glucose or tolbutamide (an insulin secretagogue) induces apoptotic ß-cell death in a Ca2+-dependent manner (38). Ob/ob mice exhibit spontaneous islet ß-cell hypertrophy and apoptosis due to insulin resistance and obesity caused by mutation of the leptin gene.
fig.ommitted2jv'a'%, http://www.100md.com
Figure 2. PERK-mediated translational and transcriptional responses to ER stress in the islet ß-cells and liver. PERK serves as a checkpoint that couples the rate of glucose metabolism and insulin synthesis with the protein folding capacity in the ER of the pancreatic ß-cells (depicted in the center and right parts). Glucose metabolism in the islet ß-cells raises intracellular calcium, [Ca++]i, and ATP that signals to the ER to regulate protein synthesis and folding. Glucose metabolism leads to the influx of Ca2+ into the ER lumen to maintain Ca2+ homeostasis. Accumulation of unfolded proteins or Ca2+ depletion in the ER leads to PERK activation that phosphorylates eIF2. Phosphorylation of eIF2 results in inhibition of general protein synthesis () and selective activation of ATF4 transcription that up-regulates CHOP gene expression, which in turn causes islet ß-cell apoptosis. ER stress also activates IRE1, which may regulate apoptosis by activation of the Janus kinase pathway (broken line). Regulation of hepatic glucose output and glycogen synthesis by the phosphorylation of eIF2 is depicted in the center and left parts of the figure. Glucagon receptor-mediated elevation of cAMP level results in activation of CREB and CREM, which activates PEPCK gene expression. Glucagon stimulates production of inositol(1 4 5 )triphosphate and [Ca2+]i via phospholypase-C (PLC) activation. Phosphorylation of eIF2 also modulates translation initiation site selection of a family of bZIP transcription factors including C/EBP and C/EBPß, and possibly CREM, all of which regulate transcription of genes involved in gluconeogenesis and glycogenolysis, including PEPCK, glucose-6-phosphatase (G-6-Pase), hepatocyte nuclear factor 3 (HNF-3), pyruvate carboxylase (PC), and glycogen synthase (GS).
Although isolated islet ß-cells from PERK-deficient mice synthesize more insulin in response to a glucose challenge in culture, serum insulin levels are low, suggesting that islets from the PERK knockout mice have impaired glucose sensing (10). Consistent with the high level of expression of PERK in the pancreas, eIF-2{alpha} is also highly expressed and phosphorylated in the pancreas of normal mice in the fasted state. Upon glucose stimulation, eIF-2{alpha} is rapidly dephosphorylated coincidentally with the up-regulation of global protein synthesis in this organ (13). Inactivation of PERK resulted in a dramatic decrease in the phosphorylated form of eIF-2{alpha} in the pancreas (13). Thus, PERK may serve as a checkpoint that couples the rate of insulin synthesis with the capacity of peptide folding and processing in the ER of the islet ß-cells. It is also possible that PERK plays a role in glucose sensing by pancreatic ß-cells as suggested by Kaufman and co-workers (11, 39). The important role of PERK in maintaining normal islet function is further corroborated by the generation of mice deficient in PERK in islet ß-cells only. These ß-cell-specific knockout mice develop diabetes but do not develop other defects, such as growth retardation and skeletal abnormalities (40).
III. eIF2 Phosphorylation and Hepatic Glucose Output1n, http://www.100md.com
In contrast to the hyperglycemia observed in PERK knockout mice, a homozygous mutation that abrogates phosphorylation of eIF2{alpha} by replacing the serine-51 phosphorylation site with an alanine (S51A knock-in mutation) causes the opposite defect in glucose homeostasis (11). These mice survive full-term pregnancy without obvious defects at birth. However, the neonates display lethal hypoglycemia and die soon after birth. Although these mice could be rescued for a short period of time with glucose injection, they became increasingly frail and died within 2 wk after birth. The requirement of PERK for normal islet ß-cell function predicts that S51A mutant mice should also develop problems with islet function. This is confirmed by lower serum insulin levels and islet ß-cell deficiency observed in S51A mutant mice. In contrast to PERK knockout mice, which contain normal islets at birth, S51A mutant mice suffer developmental defects of islet ß-cells (11). This is rather unexpected because PERK is the major eIF2{alpha} kinase in pancreatic islets. It is possible that other eIF2{alpha} kinases also play a role in regulating islet ß-cell function, because both PKR and general control nonderepressible 2 (GCN2) are expressed in the pancreas (41, 42, 43). For example, PKR is required for poly IC- and poly IC plus interferon (IFN)-induced islet cell apoptosis, implicating a role of PKR in the etiology of type 1 diabetes (43). Likewise, GCN2 is regulated by amino acid starvation that is known to regulate insulin section (44). It remains to be determined whether GCN2 knockout mice are defective in amino acid-stimulated insulin secretion. Nevertheless, deletion of each of the kinases does not interfere with normal islet development (45, 46, 47). In contrast, the S51A knock-in is the equivalent of abrogating regulation of translation initiation by all four eIF2{alpha} kinases.
As stated above, a major difference between S51A mutant mice and PERK knockout mice is the acute hepatic failure and profound hypoglycemia exhibited in the S51A mutant mice. The neonatal hypoglycemia is similar to the phenotype seen in CAAT/enhancer-binding protein (C/EBP{alpha} )- and ß (C/EBPß)-deficient mice (48, 49) and transgenic mice overexpressing a dominant-negative CREB [cAMP regulatory element (CRE)-binding protein] in the liver (50). Several enzymes involved in gluconeogenesis are down-regulated in the C/EBP knockout mice and the CREB transgenic mice (48, 50), including phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase, pyruvate carboxylase (PC), and glycogen synthase (GS) (Fig. 2). The activity of these enzymes is strongly controlled at the transcriptional level by key hormones, particularly insulin, glucagon, and glucocorticoids. Deficiency in pyruvate carboxylase or glucose-6-phosphatase leads to severe hypoglycemia (51, 52). Although PEPCK is generally considered to be the key regulator for gluconeogenesis, recent work on mice deficient in PEPCK expression in the liver suggests the enzyme may function as an integrator of hepatic energy metabolism (53). In accordance with the hypoglycemia in S51A mutant mice, the activity of PEPCK enzyme is significantly reduced (11). This occurs in the absence of the normal suppressive effect of insulin on PEPCK expression, because the S51A mutant mice suffered with hypoinsulinemia (54).
The PEPCK gene activity is controlled by the interplay among multiple members of the family of bZIP (basic leucine zipper) transcription factors including C/EBPs, CREB, and CREM (CRE modulator), the activity of which is regulated by cAMP (55). A CRE localized in the core promoter of the PEPCK gene plays a major role in up-regulation by glucagon. An increase in cAMP levels causes a transient increase in PEPCK mRNA (54). Likewise, cAMP induces expression of C/EBPs (56, 57) and CREB, which has been shown recently to transactivate the transcriptional coactivator PGC-1 (PPAR coactivator-1), a powerful regulator of hepatic gluconeogenesis (50, 58). It will be of interest to investigate whether the S51A mice have normal hepatic glucose output in response to cAMP stimulation. Therefore, a normal response to cAMP would predict defective step(s) prior to cAMP formation in the signal pathways stimulated by glucagon. Conversely, a defective response to cAMP would be indicative of downstream defect(s) that involve gluconeogenic enzymes, such as reported in the C/EBP{alpha} -deficient mice (59).
Recent studies provided insight into the mechanisms by which phosphorylation of eIF2{alpha} modulates the activity of C/EBP (60). Inhibition of eIF2{alpha} phosphorylation by overexpression of either a dominant negative mutant of PKR or S51A mutant eIF2{alpha} results in the synthesis of truncated isoforms of C/EBP{alpha} and C/EBPß in 3T3-L1 cells (60). This truncation appears to result from differential usage of initiation codons in the C/EBP{alpha} and ß genes (60), but it is not clear how phosphorylation of eIF2{alpha} affects the selection of translation initiation sites. One likely scenario is a mechanism similar to GCN4 expression in yeast (61, 62). It is especially important to determine whether different isoforms of C/EBPs have differential effects on the expression of target genes such as PEPCK.^:$gq, 百拇医药
Other ER stress-induced proteins, such as the transcription factors ATF-4 and CHOP (also known as GADD153, CREB2, and C/EBP{zeta} ), may also modulate the activity of C/EBP proteins (63, 64). Both CHOP and ATF-4 expression are down-regulated in embryonic fibroblasts derived from PERK-/- and S51A mutant mice (11, 44). CHOP attenuates C/EBP activity by forming non-DNA-binding heterodimers (64, 65, 66). CHOP cannot bind DNA by itself but dimerizes with other C/EBPs and acts as a dominant-negative inhibitor of C/EBP activity (65). Furthermore, CHOP expression is regulated by ATF-4. Interestingly, ATF-4 translation is also regulated by 5'-upstream open reading frames (uORFs) during ER stress (44). Additionally, differential usage of translation initiation sites was reported for CREM mRNA, which generates both activator and repressor proteins (67). It will be interesting to investigate whether translation initiation site selection of the CREM mRNA is also regulated by eIF2{alpha} phosphorylation. It is noteworthy that although CREM, CHOP, and ATF-4 may play a role in regulating gluconeogenesis, mice deficient for any one of these genes have not been reported to develop hypoglycemia (68, 69, 70, 71, 72), although targeted disruption of CHOP was demonstrated recently to delay ER stress-mediated diabetes in Akita mice (73). Intriguingly, inactivation of XBP-1 resulted in developmental problems with the liver (74).
IV. eIF4E Binding Protein and Insulin Sensitivity{4d|, http://www.100md.com
Diabetes and starvation cause a significant reduction in the rate of protein synthesis in rat skeletal muscle (75). Not surprisingly, muscle wasting is a common complication of uncontrolled diabetes mellitus (76), probably because of enhanced proteolysis and decreased protein synthesis (77, 78, 79). Insulin treatment inhibits proteolysis in diabetic humans and restores protein synthesis in diabetic rats (79, 80). Insulin activates eIF2B (81, 82, 83), which is the guanine nucleotide exchange factor for eIF2, and diabetes and exercise have been shown to decrease or increase eIF2B activity in the skeletal muscles, respectively (83, 84). Finally, insulin and diabetes have been shown to cause reciprocal changes in the regulation of eIF4E in rat skeletal muscle (see below and Refs. 75 and 85).{4d|, http://www.100md.com
Generally, mRNAs with structured 5'-untranslated regions are translated inefficiently (86). The eIF4F complex, composed of the scaffolding protein eIF4G, the cap-recognition protein eIF4E, and the ATP-dependent RNA helicase eIF4A, functions to increase the translation efficiency of this class of mRNAs, also referred to as weak mRNAs (Fig. 3). eIF4E is the limiting component of the eIF4F complex. Furthermore, binding of eIF4F to the 5'-cap structure plays a critical role in recruiting the 40S ribosomal subunit to the mRNA (87). In mammalian cells, eIF4F assembly is regulated by three related proteins that bind to eIF4E (4E-BPs) (88, 89). 4E-BP1, also known as PHAS-I (phosphorylated heat- and acid-stable protein regulated by insulin), was independently cloned as a major protein that undergoes phosphorylation in response to insulin (88, 90). 4E-BP1 inhibits cap-dependent translation by binding to eIF4E and preventing the association between eIF4G and eIF4E, thereby inhibiting the assembly of a functional eIF4F complex (91, 92, 93). Activation of insulin receptor-mediated signal pathways leads to the activation of insulin receptor substrate-1, phosphatidylinositol 3-kinase, Akt, and FRAP/mTOR (FKBP and rapamycin-associated protein/mammalian target of rapamycin), resulting in phosphorylation of 4E-BPs, which causes their release from eIF4E (Fig. 3). Phosphorylation of 4E-BPs is also induced by growth factors, hormones such as angiotensin II, and cytokines (94).
fig.ommittedpsj, 百拇医药
Figure 3. Insulin-stimulated 4E-BP phosphorylation and its biological effects. Insulin-stimulated phosphorylation of 4E-BPs and eIF4E leads to up-regulation of translation initiation of "weak mRNAs" that contain extensive secondary structures at their 5'-untranslated regions, and modulation of translation initiation site selection of the bZIP transcription factor, C/EBP{alpha} , and C/EBPß. C/EBPs regulate brown adipocyte differentiation by modulating transcription of the UCP1 and the PGC-1 genes. Insulin is also regulated by translation initiation of the 5'-TOP mRNAs encoding ribosomal proteins possibly by activation of S6K, which phosphorylates the S6 ribosomal proteins. The question mark (?) indicates the lack of consensus.psj, 百拇医药
4E-BP1 mRNA levels are highest in fat and skeletal muscle, two of the tissues most responsive to insulin (90), suggesting that regulation of protein synthesis by 4E-BP1 phosphorylation may play a role in regulating insulin sensitivity in these tissues. This is consistent with results obtained in mice rendered deficient for 4E-BP1 expression by homologous recombination (12). The knockout mice demonstrate enhancement in insulin sensitivity, as evidenced by lower blood glucose levels in the presence of normal serum insulin levels (12). Furthermore, increased metabolic rate and a reduction in white adipose tissue are also observed in these mice. In support of a translational role of 4E-BP1 in this phenotype, the mRNA levels of GLUT4, the insulin-responsive glucose transporter, are not altered in mice devoid of 4E-BP1-deficient mice (12). This is consistent with the findings that rapamycin abrogates insulin-mediated increase in GLUT1 protein in 3T3-L1 adipocytes through partial inhibition of GLUT1 mRNA translation, whereas chronic insulin treatment decreases GLUT-4 protein levels because of a decrease in mRNA and decrease in protein half-life (95).
Although 4E-BP1-deficient mice exhibit lower fasting blood glucose levels, it remains to be elucidated whether this results from improved insulin sensitivity (12) This can be clarified with future studies on insulin action in 4E-BP1 knockout mice on an ob/ob background. Insulin sensitivity can also be measured in the 4E-BP1 knockout mice fed a high-fat diet. It should be noted that 4E-BP1 is also expressed in the pancreatic ß-cells and its phosphorylation is controlled by insulin, glucose, and amino acids (96, 97). Thus, its inactivation may affect the function of the ß-cell as well, which could contribute to the overall phenotype of the knockout mice. Additional studies are needed to investigate whether muscle and adipocytes from the 4E-BP1 knockout mice exhibit enhanced glucose transporter-4 translocation to the cell membranes, and whether such activity is less sensitive to insulin stimulation in the knockout mice.#hk*hm#, 百拇医药
How might 4E-BP1 inactivation affect adiposity and adipocyte differentiation? 4E-BP phosphorylation is potently regulated by insulin, a hormone that induces adipogenesis (98). Thus, it is possible that abrogation of 4E-BP activity modulates adipogenesis. Additional mechanisms to account for the effect are based on the translational regulation of C/EBP expression by eIF4E during preadipocyte differentiation. As stated above, C/EBP translation into different isoforms is effected by a 5'-uORF through the activity of eIF2{alpha} . Selection of the translation initiation site of C/EBP{alpha} and C/EBPß is also regulated by eIF4E (60), suggesting a possible involvement of 4E-BP in adipocyte differentiation (Fig. 3). Consistent with this hypothesis, overexpression of eIF4E shifts C/EBP{alpha} isoform expression toward the truncated forms, whereas inhibition of eIF4E activity by rapamycin leads to accumulation of the long forms (60). Thus, overexpression of truncated forms of C/EBP{alpha} and C/EBPß disrupts terminal differentiation and induces adipogenesis in 3T3-L1 cells in culture (60).
Consistent with a role of C/EBP isoforms in regulating insulin sensitivity, insulin resistance was observed in C/EBP{alpha} -deficient fibroblasts (99, 100). In contrast, increased insulin sensitivity was observed in C/EBPß-deficient mice (101). Additionally, transgenic expression of a dominant-negative form of C/EBP allele resulted in lipoatrophy (deficiency of white adipose tissue) and, consequently, insulin resistance, fatty liver, and diabetes (102). C/EBPs are major regulators of the transcription of the gene encoding peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma} ; the receptor for thiazolidinedione drugs, which are used in the clinic as antidiabetic agents to treat insulin resistance). In accordance with the observed phenotype, translation of PGC-1, a major transcriptional coactivator of the UCP1 (uncoupling protein 1) gene, is increased in white adipose tissues of the 4E-BP knockout mice (12). PGC-1 expression is normally only found in brown fat and liver, and ectopic expression of PGC-1 in white adipocytes induces genes that are associated with the brown fat phenotype (98, 103, 104). Like PGC1, both PPAR{gamma} and C/EBP{alpha} are induced during brown fat adipogenesis. It remains to be determined whether 4E-BP inactivation also leads to PGC-1 overexpression in liver, which has been linked with increased hepatic glucose production in the ob/ob mouse (58).
Although a reduction in body weight was reported from earlier work on 4E-BP1 knockout mice, an effect on insulin sensitivity and white adipose tissue transformation was not noticed (105). It is possible that the different mouse strains used in the studies account for some of the differences; further studies are needed to clarify this discrepancy. It is also important to identify the target genes whose expression are affected by 4E-BP inactivation in the adipocyte and muscles—especially those encoding components of the insulin signal transduction pathways, such as insulin receptor substrates-1 and -2, as well as other genes containing GC-rich 5'-untranslated regions.q?f(fs, http://www.100md.com
V. S6K1 and Pancreatic ß-Cell Functionq?f(fs, http://www.100md.com
The intracellular signaling cascade leading to S6K1 phosphorylation shares many components with 4E-BP phosphorylation as both lie downstream of phosphatidylinositol 3-kinase and FRAP/mTOR (106, 107) (see Fig. 3). Activation of S6K1 is thought to enhance translation of the 5'-TOP (terminal oligopyrimidine tract) mRNA family encoding components of the translation apparatus, although this has been challenged by the recent finding that translational regulation of TOP mRNAs by amino acid starvation is independent of S6K1 activation or deficiency (108, 109). S6K1 regulates cell size and growth, e.g., inactivation of the S6K gene in Drosophila results in small flies (110); similarly, deletion of murine S6K1 yields a small mouse (111). A second gene, S6K2, is up-regulated in all tissues examined in S6K1-deficient mice (111). However, the small size of the S6K1 knockout mouse suggests that compensation by S6K2 is incomplete.
A recent report describes the requirement of S6K1 for development of mouse pancreatic ß-cells (112). Fasting blood glucose levels in S6K1 knockout mice do not differ significantly from control mice. However, S6K1-deficient mice develop hyperglycemia in response to glucose challenge because of impaired insulin secretion and decreased insulin content in the ß-cells. In accordance with the role of S6K1 in regulating insulin secretion at the translational level, glucose elicits an increase in insulin mRNA levels in isolated islets from S6K1-deficient mice. Histological analysis demonstrates smaller and fewer numbers of islet ß-cells in the knockout mice (112), an effect that is mediated by the mTOR-dependent pathway (107). It would be of interest to determine whether S6K1-deficient islets are defective in amino acid-stimulated insulin secretion, because S6K1 activity is acutely regulated by amino acid starvation (97, 113). It will also be important to study whether insulin synthesis at the translational level is affected by inactivation of S6K1, as suggested by its role in regulating translation initiation. Finally, although impaired S6K1 activity is reported in obese mice (114) and the mTOR/S6K1 signal pathway has been implicated in the impairment of insulin-stimulated glucose transport in skeletal muscle cells by amino acids (115), the S6K1 knockout mice are not insulin resistant as measured by 2-deoxy-D-glucose uptake (112), suggesting that S6K1 does not regulate insulin sensitivity.
VI. Translational Control of CD36 Expression and Diabetes-Induced Atherosclerosisiz*){ni, 百拇医药
Abnormal expression of CD36 in vascular tissues is linked to diabetes-associated atherosclerosis (116, 117, 118). In macrophages, CD36 is a scavenger receptor that mediates uptake of oxidized low-density lipoprotein involved in foam cell development (117, 119, 120). CD36 has also been identified as a receptor for advanced glycation end products that mediate diabetic vascular damage (121). Increased CD36 expression is prevalent in patients with vascular lesions and hyperglycemia (118), and in a murine model of diabetes (116). Interestingly, CD36 expression is induced by glucose in a dose-dependent manner (118). Although CD36 expression is regulated by PPAR{gamma} at the transcriptional level (120), recent evidence indicates that the effect of glucose on CD36 expression is regulated by a translational control mechanism that affects ribosomal reinitiation (118). Sucrose gradient analysis demonstrated that increased expression of CD36 under hyperglycemic conditions occurs via enhanced translation (118). The control of CD36 translation is mediated by three uORFs in the mRNA 5'-untranslated region. Mutation of all three uORFs increases CD36 basal expression significantly, but renders translation glucose independent. The first uORF plays a central role in glucose sensing because mutations that abolish the first AUG result in a loss of glucose responsiveness. This is the first direct evidence of glucose regulation of translation initiation mediated by a 5'-uORF. How the 5'-uORFs regulate translation efficiency is unknown. Hyperglycemia imposes stress on the survival apparatus of the cell; hence, it remains to be determined whether CD36 expression is regulated by eIF2{alpha} phosphorylation via a mechanism similar to C/EBPs and ATF4, as discussed above. In support of a role of hyperglycemia and C/EBP in vascular lesion formation, C/EBPß-deficient mice are hypoglycemic and show impaired ability to activate macrophages that play an important role in causing atherosclerosis (49, 122).
VII. Conclusion and Prospects#09}, 百拇医药
The role of translational control in regulating metabolism and diabetes has been uncovered by recent progress in characterizing mice rendered deficient by homologous recombination in the PERK, 4E-BP1, and S6K genes, and in eIF2{alpha} phosphorylation. Althoughinformation on translational regulation in human metabolic diseases is just beginning to emerge, the molecular basis of WRS suggests that defects in translation control may contribute to the cause of human diabetes. The C/EBP family of bZIP transcription factors plays a pivotal role in regulating energy metabolism, as adumbrated by McKnight et al. (123) more than 10 yr ago. Their roles in regulating adipogenesis and energy homeostasis are now firmly established (98). The possible involvement of C/EBPs in regulating the phenotypes observed in the eIF2{alpha} phosphorylation mutant mice and 4E-BP-deficient mice requires further investigation. There are important unanswered questions about the mechanisms by which eIF2{alpha} and 4E-BP phosphorylation regulate translation initiation site selection of the C/EBPs, which may uncover their multiple roles in regulating glucose metabolism.
Similar to other monogenic forms of diabetes, WRS is a rare example of human diabetes, which is supported by a recent investigation that failed to identify any direct linkage of PERK mutations to the cause of a group of early-onset diabetic patients (124). However, recent advances in studying UPR in the ER have begun to delineate mechanisms that underline ß-cell failure in type 2 diabetes. Thus, characterization of the involvement of CHOP in the Akita diabetic mouse (73, 125) suggests that protein overload in the ER of pancreatic ß-cells might represent a common cause of ß-cell exhaustion and apoptosis, which results from conditions such as obesity, hyperinsulinemia, hyperglycemia, and long-term treatment with sulfonylurea drugs. It will be interesting to determine whether polymorphisms in genes encoding PERK, eIF2{alpha} , 4E-BPs, S6K1, CD36, and CHOP contribute to the susceptibility for development of type 2 diabetes. An abnormal level of expression due to polymorphism in any of these genes could contribute to the susceptibility for human diabetes, as demonstrated in PERK+/- mice that show impaired glucose tolerance (10). Finally, studies on translation control and diabetes have opened a new opportunity for therapeutic development of antidiabetes drugs. For example, pharmaceuticals that inhibit CHOP activation might prevent ß-cell failure caused by abnormal metabolic conditions. Similarly, drugs that can inhibit the activity of 4E-BP1 or prevent interaction of 4E-BPs with eIF4E may provide a valuable treatment for insulin resistance and obesity, which are very serious epidemics with dramatically increased frequency in recent years.
Acknowledgmentsl%s, 百拇医药
We are grateful to Drs. David Ron and Randall Kaufman for constructive suggestions and for providing information before publication. We thank Drs. Dod Michael, Joseph Brozinick, and Kyle Sloop for critically reading the manuscript.l%s, 百拇医药
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Abstract&5.(]c;, 百拇医药
Type 2 diabetes is a polygenic disorder characterized by multiple biochemical defects including transcriptional, translational, and posttranslational abnormalities. Although major progress has been made in elucidation of factors at the transcriptional and posttranslational levels, defects at the translational level remain elusive. Mutation of a kinase that regulates translation initiation has been implicated in the etiology of a monogenic form of diabetes known as Wolcott-Rallison syndrome. Characterization of mice rendered deficient in eukaryotic initiation factors has provided model systems to study the involvement of translation in regulating insulin synthesis and secretion, hepatic function, peripheral insulin resistance, and diabetic complications. Recent progress in the understanding of endoplasmic reticulum overload by unfolded proteins has begun to uncover mechanisms leading to pancreatic ß-cell exhaustion. Future advances in this area may lead to identification of the missing links in the pathogenesis of ß-cell failures due to conditions such as hyperinsulinemia, hyperglycemia, and long-term treatment with sulfonylureas, and thus may identify novel therapeutic targets for diabetes.
I. Introduction;ix, 百拇医药
II. The Unfolded Protein Response (UPR), Pancreatic eIF2{alpha} Kinase/PKR-Like ER-Kinase (PEK/PERK), and Diabetes;ix, 百拇医药
III. eIF2{alpha} Phosphorylation and Hepatic Glucose Output;ix, 百拇医药
IV. eIF4E Binding Protein and Insulin Sensitivity;ix, 百拇医药
V. S6K1 and Pancreatic ß-Cell Function;ix, 百拇医药
VI. Translational Control of CD36 Expression and Diabetes-Induced Atherosclerosis;ix, 百拇医药
VII. Conclusion and Prospects;ix, 百拇医药
I. Introduction;ix, 百拇医药
DIABETES IS A major epidemic that affects more than 5% of the US population (1). The most common form, type 2 diabetes, is a metabolic disease caused by defective insulin secretion and insulin resistance (2), whereas type 1 diabetes is an autoimmune disorder characterized by progressive destruction of insulin-producing islet ß-cells (3, 4). Insulin plays a pivotal role in regulating glucose homeostasis, and its synthesis and secretion are regulated at the transcriptional, translational, and posttranslational levels. The importance of transcriptional regulation has been underscored by recent progress in studying a rare form of human diabetes collectively known as maturity-onset diabetes of the young. Mutations in a number of transcription factors in the pancreatic ß-cells have been identified as the common causes of maturity-onset diabetes of the young (5, 6). However, insulin synthesis is acutely regulated primarily at the translational level (7, 8). For example, insulin synthesis in islet ß-cells is activated within minutes of glucose stimulation, whereas regulation at transcriptional levels occurs more slowly (9). Although diabetes resulting from mutations that cause translational defects is rare, recent work characterizing mice rendered deficient in regulators of translation initiation factor activity (10, 11, 12, 13) has shed new light on the possible involvement of translational control in diabetes.
The etiology of type 2 diabetes remains to be elucidated. A salient feature of type 2 diabetes is insulin resistance in skeletal muscle, liver, and adipose tissues (2). Insulin resistance presents a serious challenge to the islet ß-cell’s capacity for insulin synthesis and secretion. Normoglycemia can be maintained as long as the ß-cells can secrete enough insulin to compensate for the loss of insulin sensitivity. Such excess activity imposes stress on the islet ß-cells, which compromises the ability of the ß-cells to maintain normal functions such as glucose sensing, insulin synthesis, and secretion. Diabetes occurs when insulin secretion fails to compensate for insulin resistance (14, 15), as evidenced by the fact that almost all forms of diabetes involve ß-cell failure.w!6;/&, http://www.100md.com
A hallmark of the islet ß-cell is its capacity to synthesize and secrete large quantities of insulin. Under physiological conditions, more than 5% of the total protein content in ß-cells is insulin. This imposes on the ß-cell the requirement to be able to process and fold large amounts of secreted proteins. Hence, pancreatic ß-cells may be more vulnerable to stress conditions, such as accumulation of unfolded proteins and Ca2+ depletion in the endoplasmic reticulum (ER).
In this review, we describe recent progress in characterizing the role of ER stress and translational control in diabetes by focusing on the regulation of translation initiation in maintaining glucose homeostasis.:krn, 百拇医药
II. The Unfolded Protein Response (UPR), Pancreatic eIF2 Kinase/PKR-Like-ER-Kinase (PEK/PERK), and Diabetes:krn, 百拇医药
Islet ß-cells function as specialized secretory cells and are subjected to ER stress from accumulation of unfolded proteins and Ca2+ depletion. Secreted and membrane proteins are synthesized on ER-bound ribosomes and are translocated across the ER membrane to the lumenal environment where they undergo folding, proteolytic processing, posttranslational modification, and sorting. ER activity is controlled in part by regulating Ca2+ release in response to metabolic cues and cellular stimuli. In addition, the ER transmits signals to the cytoplasm and the nucleus, leading to either cellular adaptation for survival or induction of apoptosis. Thus, the ER may be particularly sensitive to environmental perturbations such as the accumulation of unfolded proteins and/or Ca2+ depletion (16).
Great strides have been made in the past few years in the understanding of the translational regulation of ER stress. Unfolded proteins in the ER are very toxic and pose a threat to the survival of the cell. Mammalian cells have evolved intricate mechanisms that respond to the accumulation of unfolded proteins, and these are collectively known as the UPR. The UPR functions to balance protein synthesis with the cell’s capacity for folding and processing proteins. The UPR reduces ER stress by up-regulating transcription of genes encoding ER chaperones and genes involved in the degradation of unfolded proteins, while simultaneously inhibiting general protein synthesis (16). This process is coordinated by two ER-associated type I transmembrane kinases: IRE1 (inositol requiring and ER-to-nucleus signaling) and PERK (Fig. 1). IRE1 was first identified in the yeast UPR and consists of three domains including a regulatory domain, a Ser/Thr kinase domain, and a ribonuclease L (RNaseL)-like domain (17). Accumulation of unfolded proteins in yeast results in activation of the RNaseL domain of Ire1p, which catalyzes the unusual mRNA splicing of the transcription factor Hac1p. Hac1p coordinately up-regulates a family of genes encoding protein chaperones (16, 18, 19). A mammalian homolog of HAC1 has recently been identified as Xbp-1 (X-box binding protein-1) (20, 21), a member of the cAMP regulatory element binding protein/activating transcription factor (CREB/ATF) family that is highly expressed in the exocrine gland (22).
fig.ommittedwk{67, http://www.100md.com
Figure 1. UPR mediated by IRE1 and PERK. Accumulation of unfolded proteins leads to activation of IRE1 and PERK by phosphorylation. IRE1 is a tripartite kinase that contains an ER regulatory domain (REG), a serine/threonine kinase domain, and an RNaseL domain (L). The small triangle indicates the IRE1-mediated productive splicing of yeast Hac1 mRNA and mammalian XBP-1 mRNA that coordinately activates a family of genes encoding ER chaperones. Binding of unfolded proteins to PERK leads to activation of its kinase domain, which phosphorylates eIF2, resulting in general inhibition of translation initiation.wk{67, http://www.100md.com
The second arm of the UPR involves activation of PEK/PERK, which phosphorylates eukaryotic initiation factor 2{alpha} (eIF2{alpha} ) (Fig. 1). PEK was first identified in pancreatic islets by expression cloning and was characterized as a novel eIF2{alpha} kinase (23). The kinase was named PEK (pancreatic eIF2{alpha} kinase) due to its abundant expression in pancreas (24). Independently, the same kinase was also identified as an ER-associated protein kinase that phosphorylates eIF2{alpha} kinase in response to ER stress and named PERK (PKR-like-ER-kinase) (25). PERK shares significant sequence homology with IRE1 in the N terminus that defines a lumenal domain. PERK is activated by phosphorylation of its kinase domain triggered by accumulation of unfolded proteins that are proposed to displace the heat shock protein-70-like ER chaperone, Bip, from binding to the lumenal domain (26). Phosphorylation of eIF2{alpha} by PERK leads to the inhibition of general protein synthesis but, remarkably, results in selective increase of mRNA translation of activating transcription factor 4 (ATF4), which regulates UPR (25, 27).
The physiological significance of PERK in regulating ER stress is underscored by genetic characterization of a familial disease known as Wolcott-Rallison syndrome (WRS). WRS is a rare autosomal recessive disorder characterized by diabetes mellitus, multiple epiphyseal dysplasia, osteoporosis, and growth retardation (28, 29). The disease causes islet ß-cell dystrophy without major detectable defect in the glucagon-secreting {alpha} -cells (30). WRS patients often die at a young age despite treatment with insulin. Chromosomal mapping and positional cloning have localized the WRS gene to chromosome 2p12, which contains the gene encoding PEK/PERK (31, 32). Sequence analysis of the PERK gene from WRS patients has identified two mutations that cause this recessive disorder (32).-.t(*15, http://www.100md.com
The role of PERK in maintaining the function of pancreatic ß-cells has been corroborated by recent studies on knockout mice lacking functional PERK (10). PERK knockout mice are born with an apparently normal phenotype, suggesting that PERK is not required for development. Reminiscent of the diabetic pathophysiology observed in patients with WRS, the knockout mice gradually develop diabetes between 2 and 4 wk of age. The onset of diabetes coincides with decreased levels of insulin mRNA and protein. In addition to defective islet ß-cells, PERK knockout mice develop abnormalities with glucagon-secreting {alpha} -cells and problems with exocrine pancreas (10, 13). PERK knockout mice also share other features in common with human WRS, such as growth retardation and multiple skeletal dysplasias (13).
The diabetic phenotype in PERK-/- mice is primarily caused by progressive loss of islet ß-cells, as evidenced by the high number of ß-cells that score positive for an apoptosis marker (10, 13). The extensive ß-cell death in PERK-/- islets appears to be caused by the accumulation of unfolded proteins in the ER, as suggested by abnormal ER morphology in PERK-/- cells (10). The ß-cell atrophy in the PERK-/- islet could be partially caused by increased activity of a parallel stress pathway mediated by IRE1 (Fig. 2), because overexpression of IRE1 has been shown to induce apoptosis mediated partly by activation of the Janus kinase pathway (33, 34). Elevation of the levels of transcription factor CHOP (C/EBP homologous protein) by ER stress may also contribute to the loss of islet ß-cells, as demonstrated in the Akita diabetic mouse (35). Hence, Akita mice deficient in CHOP showed resistance to apoptosis from nitric oxide treatment that depletes ER Ca2+ and causes ER-stress responses (35). Additionally, it is possible that hyperglycemia and defective ER Ca2+ homeostasis also contribute to apoptosis of pancreatic ß-cells in PERK-/- islets. In support of a role of hyperglycemia in causing ß-cell apoptosis, it has been observed that PERK induction by agents that cause ER stress is more pronounced in the presence of high glucose in the media (10). Hyperglycemia has been implicated as one cause of ß-cell apoptosis in animal models of diabetes (36, 37). Exposure of ß-cells from ob/ob mice and Wistar rats to high levels of glucose or tolbutamide (an insulin secretagogue) induces apoptotic ß-cell death in a Ca2+-dependent manner (38). Ob/ob mice exhibit spontaneous islet ß-cell hypertrophy and apoptosis due to insulin resistance and obesity caused by mutation of the leptin gene.
fig.ommitted2jv'a'%, http://www.100md.com
Figure 2. PERK-mediated translational and transcriptional responses to ER stress in the islet ß-cells and liver. PERK serves as a checkpoint that couples the rate of glucose metabolism and insulin synthesis with the protein folding capacity in the ER of the pancreatic ß-cells (depicted in the center and right parts). Glucose metabolism in the islet ß-cells raises intracellular calcium, [Ca++]i, and ATP that signals to the ER to regulate protein synthesis and folding. Glucose metabolism leads to the influx of Ca2+ into the ER lumen to maintain Ca2+ homeostasis. Accumulation of unfolded proteins or Ca2+ depletion in the ER leads to PERK activation that phosphorylates eIF2. Phosphorylation of eIF2 results in inhibition of general protein synthesis () and selective activation of ATF4 transcription that up-regulates CHOP gene expression, which in turn causes islet ß-cell apoptosis. ER stress also activates IRE1, which may regulate apoptosis by activation of the Janus kinase pathway (broken line). Regulation of hepatic glucose output and glycogen synthesis by the phosphorylation of eIF2 is depicted in the center and left parts of the figure. Glucagon receptor-mediated elevation of cAMP level results in activation of CREB and CREM, which activates PEPCK gene expression. Glucagon stimulates production of inositol(1 4 5 )triphosphate and [Ca2+]i via phospholypase-C (PLC) activation. Phosphorylation of eIF2 also modulates translation initiation site selection of a family of bZIP transcription factors including C/EBP and C/EBPß, and possibly CREM, all of which regulate transcription of genes involved in gluconeogenesis and glycogenolysis, including PEPCK, glucose-6-phosphatase (G-6-Pase), hepatocyte nuclear factor 3 (HNF-3), pyruvate carboxylase (PC), and glycogen synthase (GS).
Although isolated islet ß-cells from PERK-deficient mice synthesize more insulin in response to a glucose challenge in culture, serum insulin levels are low, suggesting that islets from the PERK knockout mice have impaired glucose sensing (10). Consistent with the high level of expression of PERK in the pancreas, eIF-2{alpha} is also highly expressed and phosphorylated in the pancreas of normal mice in the fasted state. Upon glucose stimulation, eIF-2{alpha} is rapidly dephosphorylated coincidentally with the up-regulation of global protein synthesis in this organ (13). Inactivation of PERK resulted in a dramatic decrease in the phosphorylated form of eIF-2{alpha} in the pancreas (13). Thus, PERK may serve as a checkpoint that couples the rate of insulin synthesis with the capacity of peptide folding and processing in the ER of the islet ß-cells. It is also possible that PERK plays a role in glucose sensing by pancreatic ß-cells as suggested by Kaufman and co-workers (11, 39). The important role of PERK in maintaining normal islet function is further corroborated by the generation of mice deficient in PERK in islet ß-cells only. These ß-cell-specific knockout mice develop diabetes but do not develop other defects, such as growth retardation and skeletal abnormalities (40).
III. eIF2 Phosphorylation and Hepatic Glucose Output1n, http://www.100md.com
In contrast to the hyperglycemia observed in PERK knockout mice, a homozygous mutation that abrogates phosphorylation of eIF2{alpha} by replacing the serine-51 phosphorylation site with an alanine (S51A knock-in mutation) causes the opposite defect in glucose homeostasis (11). These mice survive full-term pregnancy without obvious defects at birth. However, the neonates display lethal hypoglycemia and die soon after birth. Although these mice could be rescued for a short period of time with glucose injection, they became increasingly frail and died within 2 wk after birth. The requirement of PERK for normal islet ß-cell function predicts that S51A mutant mice should also develop problems with islet function. This is confirmed by lower serum insulin levels and islet ß-cell deficiency observed in S51A mutant mice. In contrast to PERK knockout mice, which contain normal islets at birth, S51A mutant mice suffer developmental defects of islet ß-cells (11). This is rather unexpected because PERK is the major eIF2{alpha} kinase in pancreatic islets. It is possible that other eIF2{alpha} kinases also play a role in regulating islet ß-cell function, because both PKR and general control nonderepressible 2 (GCN2) are expressed in the pancreas (41, 42, 43). For example, PKR is required for poly IC- and poly IC plus interferon (IFN)-induced islet cell apoptosis, implicating a role of PKR in the etiology of type 1 diabetes (43). Likewise, GCN2 is regulated by amino acid starvation that is known to regulate insulin section (44). It remains to be determined whether GCN2 knockout mice are defective in amino acid-stimulated insulin secretion. Nevertheless, deletion of each of the kinases does not interfere with normal islet development (45, 46, 47). In contrast, the S51A knock-in is the equivalent of abrogating regulation of translation initiation by all four eIF2{alpha} kinases.
As stated above, a major difference between S51A mutant mice and PERK knockout mice is the acute hepatic failure and profound hypoglycemia exhibited in the S51A mutant mice. The neonatal hypoglycemia is similar to the phenotype seen in CAAT/enhancer-binding protein (C/EBP{alpha} )- and ß (C/EBPß)-deficient mice (48, 49) and transgenic mice overexpressing a dominant-negative CREB [cAMP regulatory element (CRE)-binding protein] in the liver (50). Several enzymes involved in gluconeogenesis are down-regulated in the C/EBP knockout mice and the CREB transgenic mice (48, 50), including phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase, pyruvate carboxylase (PC), and glycogen synthase (GS) (Fig. 2). The activity of these enzymes is strongly controlled at the transcriptional level by key hormones, particularly insulin, glucagon, and glucocorticoids. Deficiency in pyruvate carboxylase or glucose-6-phosphatase leads to severe hypoglycemia (51, 52). Although PEPCK is generally considered to be the key regulator for gluconeogenesis, recent work on mice deficient in PEPCK expression in the liver suggests the enzyme may function as an integrator of hepatic energy metabolism (53). In accordance with the hypoglycemia in S51A mutant mice, the activity of PEPCK enzyme is significantly reduced (11). This occurs in the absence of the normal suppressive effect of insulin on PEPCK expression, because the S51A mutant mice suffered with hypoinsulinemia (54).
The PEPCK gene activity is controlled by the interplay among multiple members of the family of bZIP (basic leucine zipper) transcription factors including C/EBPs, CREB, and CREM (CRE modulator), the activity of which is regulated by cAMP (55). A CRE localized in the core promoter of the PEPCK gene plays a major role in up-regulation by glucagon. An increase in cAMP levels causes a transient increase in PEPCK mRNA (54). Likewise, cAMP induces expression of C/EBPs (56, 57) and CREB, which has been shown recently to transactivate the transcriptional coactivator PGC-1 (PPAR coactivator-1), a powerful regulator of hepatic gluconeogenesis (50, 58). It will be of interest to investigate whether the S51A mice have normal hepatic glucose output in response to cAMP stimulation. Therefore, a normal response to cAMP would predict defective step(s) prior to cAMP formation in the signal pathways stimulated by glucagon. Conversely, a defective response to cAMP would be indicative of downstream defect(s) that involve gluconeogenic enzymes, such as reported in the C/EBP{alpha} -deficient mice (59).
Recent studies provided insight into the mechanisms by which phosphorylation of eIF2{alpha} modulates the activity of C/EBP (60). Inhibition of eIF2{alpha} phosphorylation by overexpression of either a dominant negative mutant of PKR or S51A mutant eIF2{alpha} results in the synthesis of truncated isoforms of C/EBP{alpha} and C/EBPß in 3T3-L1 cells (60). This truncation appears to result from differential usage of initiation codons in the C/EBP{alpha} and ß genes (60), but it is not clear how phosphorylation of eIF2{alpha} affects the selection of translation initiation sites. One likely scenario is a mechanism similar to GCN4 expression in yeast (61, 62). It is especially important to determine whether different isoforms of C/EBPs have differential effects on the expression of target genes such as PEPCK.^:$gq, 百拇医药
Other ER stress-induced proteins, such as the transcription factors ATF-4 and CHOP (also known as GADD153, CREB2, and C/EBP{zeta} ), may also modulate the activity of C/EBP proteins (63, 64). Both CHOP and ATF-4 expression are down-regulated in embryonic fibroblasts derived from PERK-/- and S51A mutant mice (11, 44). CHOP attenuates C/EBP activity by forming non-DNA-binding heterodimers (64, 65, 66). CHOP cannot bind DNA by itself but dimerizes with other C/EBPs and acts as a dominant-negative inhibitor of C/EBP activity (65). Furthermore, CHOP expression is regulated by ATF-4. Interestingly, ATF-4 translation is also regulated by 5'-upstream open reading frames (uORFs) during ER stress (44). Additionally, differential usage of translation initiation sites was reported for CREM mRNA, which generates both activator and repressor proteins (67). It will be interesting to investigate whether translation initiation site selection of the CREM mRNA is also regulated by eIF2{alpha} phosphorylation. It is noteworthy that although CREM, CHOP, and ATF-4 may play a role in regulating gluconeogenesis, mice deficient for any one of these genes have not been reported to develop hypoglycemia (68, 69, 70, 71, 72), although targeted disruption of CHOP was demonstrated recently to delay ER stress-mediated diabetes in Akita mice (73). Intriguingly, inactivation of XBP-1 resulted in developmental problems with the liver (74).
IV. eIF4E Binding Protein and Insulin Sensitivity{4d|, http://www.100md.com
Diabetes and starvation cause a significant reduction in the rate of protein synthesis in rat skeletal muscle (75). Not surprisingly, muscle wasting is a common complication of uncontrolled diabetes mellitus (76), probably because of enhanced proteolysis and decreased protein synthesis (77, 78, 79). Insulin treatment inhibits proteolysis in diabetic humans and restores protein synthesis in diabetic rats (79, 80). Insulin activates eIF2B (81, 82, 83), which is the guanine nucleotide exchange factor for eIF2, and diabetes and exercise have been shown to decrease or increase eIF2B activity in the skeletal muscles, respectively (83, 84). Finally, insulin and diabetes have been shown to cause reciprocal changes in the regulation of eIF4E in rat skeletal muscle (see below and Refs. 75 and 85).{4d|, http://www.100md.com
Generally, mRNAs with structured 5'-untranslated regions are translated inefficiently (86). The eIF4F complex, composed of the scaffolding protein eIF4G, the cap-recognition protein eIF4E, and the ATP-dependent RNA helicase eIF4A, functions to increase the translation efficiency of this class of mRNAs, also referred to as weak mRNAs (Fig. 3). eIF4E is the limiting component of the eIF4F complex. Furthermore, binding of eIF4F to the 5'-cap structure plays a critical role in recruiting the 40S ribosomal subunit to the mRNA (87). In mammalian cells, eIF4F assembly is regulated by three related proteins that bind to eIF4E (4E-BPs) (88, 89). 4E-BP1, also known as PHAS-I (phosphorylated heat- and acid-stable protein regulated by insulin), was independently cloned as a major protein that undergoes phosphorylation in response to insulin (88, 90). 4E-BP1 inhibits cap-dependent translation by binding to eIF4E and preventing the association between eIF4G and eIF4E, thereby inhibiting the assembly of a functional eIF4F complex (91, 92, 93). Activation of insulin receptor-mediated signal pathways leads to the activation of insulin receptor substrate-1, phosphatidylinositol 3-kinase, Akt, and FRAP/mTOR (FKBP and rapamycin-associated protein/mammalian target of rapamycin), resulting in phosphorylation of 4E-BPs, which causes their release from eIF4E (Fig. 3). Phosphorylation of 4E-BPs is also induced by growth factors, hormones such as angiotensin II, and cytokines (94).
fig.ommittedpsj, 百拇医药
Figure 3. Insulin-stimulated 4E-BP phosphorylation and its biological effects. Insulin-stimulated phosphorylation of 4E-BPs and eIF4E leads to up-regulation of translation initiation of "weak mRNAs" that contain extensive secondary structures at their 5'-untranslated regions, and modulation of translation initiation site selection of the bZIP transcription factor, C/EBP{alpha} , and C/EBPß. C/EBPs regulate brown adipocyte differentiation by modulating transcription of the UCP1 and the PGC-1 genes. Insulin is also regulated by translation initiation of the 5'-TOP mRNAs encoding ribosomal proteins possibly by activation of S6K, which phosphorylates the S6 ribosomal proteins. The question mark (?) indicates the lack of consensus.psj, 百拇医药
4E-BP1 mRNA levels are highest in fat and skeletal muscle, two of the tissues most responsive to insulin (90), suggesting that regulation of protein synthesis by 4E-BP1 phosphorylation may play a role in regulating insulin sensitivity in these tissues. This is consistent with results obtained in mice rendered deficient for 4E-BP1 expression by homologous recombination (12). The knockout mice demonstrate enhancement in insulin sensitivity, as evidenced by lower blood glucose levels in the presence of normal serum insulin levels (12). Furthermore, increased metabolic rate and a reduction in white adipose tissue are also observed in these mice. In support of a translational role of 4E-BP1 in this phenotype, the mRNA levels of GLUT4, the insulin-responsive glucose transporter, are not altered in mice devoid of 4E-BP1-deficient mice (12). This is consistent with the findings that rapamycin abrogates insulin-mediated increase in GLUT1 protein in 3T3-L1 adipocytes through partial inhibition of GLUT1 mRNA translation, whereas chronic insulin treatment decreases GLUT-4 protein levels because of a decrease in mRNA and decrease in protein half-life (95).
Although 4E-BP1-deficient mice exhibit lower fasting blood glucose levels, it remains to be elucidated whether this results from improved insulin sensitivity (12) This can be clarified with future studies on insulin action in 4E-BP1 knockout mice on an ob/ob background. Insulin sensitivity can also be measured in the 4E-BP1 knockout mice fed a high-fat diet. It should be noted that 4E-BP1 is also expressed in the pancreatic ß-cells and its phosphorylation is controlled by insulin, glucose, and amino acids (96, 97). Thus, its inactivation may affect the function of the ß-cell as well, which could contribute to the overall phenotype of the knockout mice. Additional studies are needed to investigate whether muscle and adipocytes from the 4E-BP1 knockout mice exhibit enhanced glucose transporter-4 translocation to the cell membranes, and whether such activity is less sensitive to insulin stimulation in the knockout mice.#hk*hm#, 百拇医药
How might 4E-BP1 inactivation affect adiposity and adipocyte differentiation? 4E-BP phosphorylation is potently regulated by insulin, a hormone that induces adipogenesis (98). Thus, it is possible that abrogation of 4E-BP activity modulates adipogenesis. Additional mechanisms to account for the effect are based on the translational regulation of C/EBP expression by eIF4E during preadipocyte differentiation. As stated above, C/EBP translation into different isoforms is effected by a 5'-uORF through the activity of eIF2{alpha} . Selection of the translation initiation site of C/EBP{alpha} and C/EBPß is also regulated by eIF4E (60), suggesting a possible involvement of 4E-BP in adipocyte differentiation (Fig. 3). Consistent with this hypothesis, overexpression of eIF4E shifts C/EBP{alpha} isoform expression toward the truncated forms, whereas inhibition of eIF4E activity by rapamycin leads to accumulation of the long forms (60). Thus, overexpression of truncated forms of C/EBP{alpha} and C/EBPß disrupts terminal differentiation and induces adipogenesis in 3T3-L1 cells in culture (60).
Consistent with a role of C/EBP isoforms in regulating insulin sensitivity, insulin resistance was observed in C/EBP{alpha} -deficient fibroblasts (99, 100). In contrast, increased insulin sensitivity was observed in C/EBPß-deficient mice (101). Additionally, transgenic expression of a dominant-negative form of C/EBP allele resulted in lipoatrophy (deficiency of white adipose tissue) and, consequently, insulin resistance, fatty liver, and diabetes (102). C/EBPs are major regulators of the transcription of the gene encoding peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma} ; the receptor for thiazolidinedione drugs, which are used in the clinic as antidiabetic agents to treat insulin resistance). In accordance with the observed phenotype, translation of PGC-1, a major transcriptional coactivator of the UCP1 (uncoupling protein 1) gene, is increased in white adipose tissues of the 4E-BP knockout mice (12). PGC-1 expression is normally only found in brown fat and liver, and ectopic expression of PGC-1 in white adipocytes induces genes that are associated with the brown fat phenotype (98, 103, 104). Like PGC1, both PPAR{gamma} and C/EBP{alpha} are induced during brown fat adipogenesis. It remains to be determined whether 4E-BP inactivation also leads to PGC-1 overexpression in liver, which has been linked with increased hepatic glucose production in the ob/ob mouse (58).
Although a reduction in body weight was reported from earlier work on 4E-BP1 knockout mice, an effect on insulin sensitivity and white adipose tissue transformation was not noticed (105). It is possible that the different mouse strains used in the studies account for some of the differences; further studies are needed to clarify this discrepancy. It is also important to identify the target genes whose expression are affected by 4E-BP inactivation in the adipocyte and muscles—especially those encoding components of the insulin signal transduction pathways, such as insulin receptor substrates-1 and -2, as well as other genes containing GC-rich 5'-untranslated regions.q?f(fs, http://www.100md.com
V. S6K1 and Pancreatic ß-Cell Functionq?f(fs, http://www.100md.com
The intracellular signaling cascade leading to S6K1 phosphorylation shares many components with 4E-BP phosphorylation as both lie downstream of phosphatidylinositol 3-kinase and FRAP/mTOR (106, 107) (see Fig. 3). Activation of S6K1 is thought to enhance translation of the 5'-TOP (terminal oligopyrimidine tract) mRNA family encoding components of the translation apparatus, although this has been challenged by the recent finding that translational regulation of TOP mRNAs by amino acid starvation is independent of S6K1 activation or deficiency (108, 109). S6K1 regulates cell size and growth, e.g., inactivation of the S6K gene in Drosophila results in small flies (110); similarly, deletion of murine S6K1 yields a small mouse (111). A second gene, S6K2, is up-regulated in all tissues examined in S6K1-deficient mice (111). However, the small size of the S6K1 knockout mouse suggests that compensation by S6K2 is incomplete.
A recent report describes the requirement of S6K1 for development of mouse pancreatic ß-cells (112). Fasting blood glucose levels in S6K1 knockout mice do not differ significantly from control mice. However, S6K1-deficient mice develop hyperglycemia in response to glucose challenge because of impaired insulin secretion and decreased insulin content in the ß-cells. In accordance with the role of S6K1 in regulating insulin secretion at the translational level, glucose elicits an increase in insulin mRNA levels in isolated islets from S6K1-deficient mice. Histological analysis demonstrates smaller and fewer numbers of islet ß-cells in the knockout mice (112), an effect that is mediated by the mTOR-dependent pathway (107). It would be of interest to determine whether S6K1-deficient islets are defective in amino acid-stimulated insulin secretion, because S6K1 activity is acutely regulated by amino acid starvation (97, 113). It will also be important to study whether insulin synthesis at the translational level is affected by inactivation of S6K1, as suggested by its role in regulating translation initiation. Finally, although impaired S6K1 activity is reported in obese mice (114) and the mTOR/S6K1 signal pathway has been implicated in the impairment of insulin-stimulated glucose transport in skeletal muscle cells by amino acids (115), the S6K1 knockout mice are not insulin resistant as measured by 2-deoxy-D-glucose uptake (112), suggesting that S6K1 does not regulate insulin sensitivity.
VI. Translational Control of CD36 Expression and Diabetes-Induced Atherosclerosisiz*){ni, 百拇医药
Abnormal expression of CD36 in vascular tissues is linked to diabetes-associated atherosclerosis (116, 117, 118). In macrophages, CD36 is a scavenger receptor that mediates uptake of oxidized low-density lipoprotein involved in foam cell development (117, 119, 120). CD36 has also been identified as a receptor for advanced glycation end products that mediate diabetic vascular damage (121). Increased CD36 expression is prevalent in patients with vascular lesions and hyperglycemia (118), and in a murine model of diabetes (116). Interestingly, CD36 expression is induced by glucose in a dose-dependent manner (118). Although CD36 expression is regulated by PPAR{gamma} at the transcriptional level (120), recent evidence indicates that the effect of glucose on CD36 expression is regulated by a translational control mechanism that affects ribosomal reinitiation (118). Sucrose gradient analysis demonstrated that increased expression of CD36 under hyperglycemic conditions occurs via enhanced translation (118). The control of CD36 translation is mediated by three uORFs in the mRNA 5'-untranslated region. Mutation of all three uORFs increases CD36 basal expression significantly, but renders translation glucose independent. The first uORF plays a central role in glucose sensing because mutations that abolish the first AUG result in a loss of glucose responsiveness. This is the first direct evidence of glucose regulation of translation initiation mediated by a 5'-uORF. How the 5'-uORFs regulate translation efficiency is unknown. Hyperglycemia imposes stress on the survival apparatus of the cell; hence, it remains to be determined whether CD36 expression is regulated by eIF2{alpha} phosphorylation via a mechanism similar to C/EBPs and ATF4, as discussed above. In support of a role of hyperglycemia and C/EBP in vascular lesion formation, C/EBPß-deficient mice are hypoglycemic and show impaired ability to activate macrophages that play an important role in causing atherosclerosis (49, 122).
VII. Conclusion and Prospects#09}, 百拇医药
The role of translational control in regulating metabolism and diabetes has been uncovered by recent progress in characterizing mice rendered deficient by homologous recombination in the PERK, 4E-BP1, and S6K genes, and in eIF2{alpha} phosphorylation. Althoughinformation on translational regulation in human metabolic diseases is just beginning to emerge, the molecular basis of WRS suggests that defects in translation control may contribute to the cause of human diabetes. The C/EBP family of bZIP transcription factors plays a pivotal role in regulating energy metabolism, as adumbrated by McKnight et al. (123) more than 10 yr ago. Their roles in regulating adipogenesis and energy homeostasis are now firmly established (98). The possible involvement of C/EBPs in regulating the phenotypes observed in the eIF2{alpha} phosphorylation mutant mice and 4E-BP-deficient mice requires further investigation. There are important unanswered questions about the mechanisms by which eIF2{alpha} and 4E-BP phosphorylation regulate translation initiation site selection of the C/EBPs, which may uncover their multiple roles in regulating glucose metabolism.
Similar to other monogenic forms of diabetes, WRS is a rare example of human diabetes, which is supported by a recent investigation that failed to identify any direct linkage of PERK mutations to the cause of a group of early-onset diabetic patients (124). However, recent advances in studying UPR in the ER have begun to delineate mechanisms that underline ß-cell failure in type 2 diabetes. Thus, characterization of the involvement of CHOP in the Akita diabetic mouse (73, 125) suggests that protein overload in the ER of pancreatic ß-cells might represent a common cause of ß-cell exhaustion and apoptosis, which results from conditions such as obesity, hyperinsulinemia, hyperglycemia, and long-term treatment with sulfonylurea drugs. It will be interesting to determine whether polymorphisms in genes encoding PERK, eIF2{alpha} , 4E-BPs, S6K1, CD36, and CHOP contribute to the susceptibility for development of type 2 diabetes. An abnormal level of expression due to polymorphism in any of these genes could contribute to the susceptibility for human diabetes, as demonstrated in PERK+/- mice that show impaired glucose tolerance (10). Finally, studies on translation control and diabetes have opened a new opportunity for therapeutic development of antidiabetes drugs. For example, pharmaceuticals that inhibit CHOP activation might prevent ß-cell failure caused by abnormal metabolic conditions. Similarly, drugs that can inhibit the activity of 4E-BP1 or prevent interaction of 4E-BPs with eIF4E may provide a valuable treatment for insulin resistance and obesity, which are very serious epidemics with dramatically increased frequency in recent years.
Acknowledgmentsl%s, 百拇医药
We are grateful to Drs. David Ron and Randall Kaufman for constructive suggestions and for providing information before publication. We thank Drs. Dod Michael, Joseph Brozinick, and Kyle Sloop for critically reading the manuscript.l%s, 百拇医药
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