Fatty Acid Metabolism in Cystic Fibrosis
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《新英格兰医药杂志》
In 1989, when the gene locus for cystic fibrosis was identified, expectations were great for rapid progress in understanding and effectively treating the disease. It was generally believed that cystic fibrosis was a monogenic disease, which would possibly soon be treatable by gene therapy. Now, 15 years later, it has turned out that nature is much more complicated than we had predicted. For example, even though more than 1200 mutations have been identified in the cystic fibrosis transmembrane conductance regulator gene (CFTR), the search for a relation between the different phenotypes and mutations has mainly failed. Furthermore, siblings with identical mutations have been shown to have different phenotypes, and among the modifier genes that have been examined in this context, only a few candidate genes have been identified.
There also has been renewed interest in the abnormal metabolism of fatty acids in patients with cystic fibrosis. When this phenomenon was first noted more than 40 years ago, the primary abnormalities identified were decreased linoleic acid levels in different tissue compartments. Because of its strong association with pancreatic insufficiency, present in more than 80 percent of patients with cystic fibrosis, these abnormalities have been presumed to be secondary to fat malabsorption and hence not a primary abnormality due to CFTR mutations.1
During the past 30 years, several reports have given support to the view that the essential fatty acid abnormalities observed in patients with cystic fibrosis may have a more fundamental role in the symptoms and progression of the disease.2 For example, among newborn infants with cystic fibrosis and in prospective studies of infants with cystic fibrosis who are identified by neonatal screening, low linoleic acid concentrations are present at birth and are more pronounced in infants who present with meconium ileus.3 Abnormal turnover of essential fatty acids has been reported by several groups,4,5 and increased release of arachidonic acid, the most important metabolic product of linoleic acid, has been described in different in vitro systems.6,7,8
These data, along with the observation that mice with a targeted deletion of the CFTR gene have an abnormal ratio of arachidonic acid to docosahexaenoic acid in pancreatic tissue, have led to the speculation that abnormalities in the metabolism of arachidonic acid and docosahexaenoic acid may be primary in cystic fibrosis.6,9 As reported in this issue of the Journal, Freedman et al.9 demonstrate an increased ratio of arachidonic to docosahexaenoic acid in nasal and rectal epithelium, tissues that express CFTR, in patients with cystic fibrosis.
When considering the findings reported by Freedman et al., it is important to note that total plasma fatty acid concentrations mainly mirror the triglyceride composition, which is dependent on recent dietary fat intake. A high linoleic acid intake may depress the synthesis of docosahexaenoic acid. The Western diet, especially that in the United States, has been reported to contain very high levels of linoleic acid, with ratios of n–6 to n–3 essential fatty acids in the range of 10 to 20 or even higher.10 Despite these very high levels, which are potential risk factors, diet is unlikely to explain the differences in the present study between control subjects without a recognized mutation in CFTR and patients who were obligate heterozygotes for known CFTR mutations.
The marked reduction in plasma levels of docosahexaenoic acid in the patients studied by Freedman et al. differs from the findings in most other studies of patients with cystic fibrosis. In some of these studies, the low plasma docosahexaenoic acid levels can be partially normalized by compensating for the low linoleic acid levels.1 However, this does not appear to be a satisfactory explanation for the results reported by Freedman et al., since they do not report a significant decrease in plasma linoleic acid. The reason for the absence of a significant decrease might be that the investigators do not report whether the plasma and biopsy specimens they analyzed were from the same patients. Furthermore, the small amount of biopsy material was not selected from patients with the same CFTR mutations; such a difference has been shown to influence fatty acid abnormalities.11 Data on fatty acids in tissues other than blood are sparse, and values for docosahexaenoic acid as low as those found in epithelial tissues in this study have previously been reported only in tissues obtained from patients with cystic fibrosis at autopsy.1,12
Arachidonic acid is the substrate for many active prostanoids, including prostaglandin E2, thromboxane A2, leukotriene B4, and the cysteinyl leukotrienes.13 The release of arachidonic acid is the rate-limiting step in prostanoid synthesis. In the process of the transformation of different groups of long-chain fatty acids, all compete for the same elongases and desaturases (as shown in Figure 1 in the article by Freedman et al.), an increase of one group of fatty acids, those of the n–3 series, has been shown to slow the transformation of n–6 fatty acids. There is both an increase in arachidonic acid and a marked increase of the prostanoids,14 which might contribute to the inflammation that characterizes cystic fibrosis. Since docosahexaenoic acid, in an in vitro system, has been shown to inhibit the synthesis of prostanoids but not of leukotrienes,15 a decrease in docosahexaenoic acid might contribute to the increased prostanoid synthesis in cystic fibrosis. Nevertheless, for this idea to be credible, it has to be shown that docosahexaenoic acid can hamper the reaction in cells in patients with cystic fibrosis.
In the analysis of fatty acids from nasal scrapings in the study by Freedman et al., patients with asthma and those with upper respiratory infection had ratios of arachidonic to docosahexaenoic acid that were similar to those in the obligate heterozygotes. Freedman et al. do not report the degree of inflammation in the different types of samples, but since most of the patients with asthma were treated with corticosteroids, such treatment may have biased their results. Furthermore, since patients with asthma and other forms of allergy have repeatedly been reported to have an abnormal plasma fatty acid pattern,16 the findings of Freedman et al. in patients with cystic fibrosis need to be considered in the context of these other observations.
What do these findings mean for the treatment of patients with cystic fibrosis? The long-chain essential fatty acids and their eicosanoids have been shown to have a profound influence on membrane receptor function, transmembrane signaling mechanisms, phospholipase activation, calcium release, ion channels, and gene expression. Disturbances of this complex interactive system can have fundamental importance for cell function. In patients with cystic fibrosis, it seems reasonable to try to normalize plasma levels of essential fatty acids, although we know that the fatty acid profile of different tissues may not be reflected in the plasma, or even in the phospholipids of red-cell membranes. Until we understand the defective fatty acid metabolism in cystic fibrosis and how these abnormalities may interfere with CFTR function, specific treatment, especially with pharmacologic amounts of these acids, should be approached with great caution.
Source Information
From the Department of Pediatrics, Institute of the Health of Women and Children, G?teborg University, G?teborg, Sweden.
References
Farrell PM, Mischler EH, Engle MJ, Brown J, Lau S-M. Fatty acid abnormalities in cystic fibrosis. Pediatr Res 1985;19:104-109.
Strandvik B. Long chain fatty acid metabolism and essential fatty acid deficiency with special emphasis on cystic fibrosis. In: Bracco U, Decklelbaum RJ, eds. Polyunsaturated fatty acids in human nutrition. Vol. 28 of Nestlé Nutrition Workshop Series. New York: Raven Press, 1992:159-67.
Lai H-C, Kosorok MR, Laxova A, Davis LA, FitzSimmon SC, Farrell PM. Nutritional status of patients with cystic fibrosis with meconium ileus: a comparison with patients without meconium ileus and diagnosed early through neonatal screening. Pediatrics 2000;105:53-61.
Ulane MM, Butler JB, Peri A, Miele L, Ulane RE, Hubbard VS. Cystic fibrosis and phosphatidylcholine biosynthesis. Clin Chim Acta 1994;230:109-116.
Bhura-Bandali FN, Suh M, Man SFP, Clandinin MT. The F508 mutation in the cystic fibrosis transmembrane conductance regulator alters control of essential fatty acid utilization in epithelial cells. J Nutr 2000;130:2870-2875.
Carlstedt-Duke J, Br?nneg?rd M, Strandvik B. Pathological regulation of arachidonic acid release in cystic fibrosis: the putative basic defect. Proc Natl Acad Sci U S A 1986;83:9202-9206.
Levistre R, Lemnaouar M, Rybkine T, Béréziat G, Masliah J. Increase of bradykinin-stimulated arachidonic acid release in a delta F508 cystic fibrosis epithelial cell line. Biochim Biophys Acta 1993;1181:233-239.
Miele L, Cordella-Miele E, Xing M, Frizzell R, Mukherjee AB. Cystic fibrosis gene mutation (deltaF508) is associated with an intrinsic abnormality in Ca2+-induced arachidonic acid release by epithelial cells. DNA Cell Biol 1997;16:749-759.
Freedman SD, Blanco PG, Zaman MM, et al. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med 2004;350:560-569.
Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr 1999;70:Suppl:560S-569S.
Strandvik B, Gronowitz E, Enlund F, Martinsson T, Wahlstr?m J. Essential fatty acid deficiency in relation to genotype in patients with cystic fibrosis. J Pediatr 2001;139:650-655.
Underwood BA, Denning CR, Navab M. Polyunsaturated fatty acids and tocopherol levels in patients with cystic fibrosis. Ann N Y Acad Sci 1972;203:237-247.
Weber PC. The modification of the arachidonic acid cascade by n-3 fatty acids. Adv Prostaglandin Thromboxane Leukot Res 1990;20:232-240.
Strandvik B, Svensson E, Seyberth HW. Prostanoid biosynthesis in patients with cystic fibrosis. Prostaglandins Leukot Essent Fatty Acids 1996;55:419-425.
Corey EJ, Shih C, Cashman JR. Docosahexaenoic acid is a strong inhibitor of prostaglandin but not leukotriene biosynthesis. Proc Natl Acad Sci U S A 1983;80:3581-3584.
Yu G, Bj?rksten B. Polyunsaturated fatty acids in school children in relation to allergy and serum IgE levels. Pediatr Allergy Immunol 1998;9:133-138.(Birgitta Strandvik, M.D.,)
There also has been renewed interest in the abnormal metabolism of fatty acids in patients with cystic fibrosis. When this phenomenon was first noted more than 40 years ago, the primary abnormalities identified were decreased linoleic acid levels in different tissue compartments. Because of its strong association with pancreatic insufficiency, present in more than 80 percent of patients with cystic fibrosis, these abnormalities have been presumed to be secondary to fat malabsorption and hence not a primary abnormality due to CFTR mutations.1
During the past 30 years, several reports have given support to the view that the essential fatty acid abnormalities observed in patients with cystic fibrosis may have a more fundamental role in the symptoms and progression of the disease.2 For example, among newborn infants with cystic fibrosis and in prospective studies of infants with cystic fibrosis who are identified by neonatal screening, low linoleic acid concentrations are present at birth and are more pronounced in infants who present with meconium ileus.3 Abnormal turnover of essential fatty acids has been reported by several groups,4,5 and increased release of arachidonic acid, the most important metabolic product of linoleic acid, has been described in different in vitro systems.6,7,8
These data, along with the observation that mice with a targeted deletion of the CFTR gene have an abnormal ratio of arachidonic acid to docosahexaenoic acid in pancreatic tissue, have led to the speculation that abnormalities in the metabolism of arachidonic acid and docosahexaenoic acid may be primary in cystic fibrosis.6,9 As reported in this issue of the Journal, Freedman et al.9 demonstrate an increased ratio of arachidonic to docosahexaenoic acid in nasal and rectal epithelium, tissues that express CFTR, in patients with cystic fibrosis.
When considering the findings reported by Freedman et al., it is important to note that total plasma fatty acid concentrations mainly mirror the triglyceride composition, which is dependent on recent dietary fat intake. A high linoleic acid intake may depress the synthesis of docosahexaenoic acid. The Western diet, especially that in the United States, has been reported to contain very high levels of linoleic acid, with ratios of n–6 to n–3 essential fatty acids in the range of 10 to 20 or even higher.10 Despite these very high levels, which are potential risk factors, diet is unlikely to explain the differences in the present study between control subjects without a recognized mutation in CFTR and patients who were obligate heterozygotes for known CFTR mutations.
The marked reduction in plasma levels of docosahexaenoic acid in the patients studied by Freedman et al. differs from the findings in most other studies of patients with cystic fibrosis. In some of these studies, the low plasma docosahexaenoic acid levels can be partially normalized by compensating for the low linoleic acid levels.1 However, this does not appear to be a satisfactory explanation for the results reported by Freedman et al., since they do not report a significant decrease in plasma linoleic acid. The reason for the absence of a significant decrease might be that the investigators do not report whether the plasma and biopsy specimens they analyzed were from the same patients. Furthermore, the small amount of biopsy material was not selected from patients with the same CFTR mutations; such a difference has been shown to influence fatty acid abnormalities.11 Data on fatty acids in tissues other than blood are sparse, and values for docosahexaenoic acid as low as those found in epithelial tissues in this study have previously been reported only in tissues obtained from patients with cystic fibrosis at autopsy.1,12
Arachidonic acid is the substrate for many active prostanoids, including prostaglandin E2, thromboxane A2, leukotriene B4, and the cysteinyl leukotrienes.13 The release of arachidonic acid is the rate-limiting step in prostanoid synthesis. In the process of the transformation of different groups of long-chain fatty acids, all compete for the same elongases and desaturases (as shown in Figure 1 in the article by Freedman et al.), an increase of one group of fatty acids, those of the n–3 series, has been shown to slow the transformation of n–6 fatty acids. There is both an increase in arachidonic acid and a marked increase of the prostanoids,14 which might contribute to the inflammation that characterizes cystic fibrosis. Since docosahexaenoic acid, in an in vitro system, has been shown to inhibit the synthesis of prostanoids but not of leukotrienes,15 a decrease in docosahexaenoic acid might contribute to the increased prostanoid synthesis in cystic fibrosis. Nevertheless, for this idea to be credible, it has to be shown that docosahexaenoic acid can hamper the reaction in cells in patients with cystic fibrosis.
In the analysis of fatty acids from nasal scrapings in the study by Freedman et al., patients with asthma and those with upper respiratory infection had ratios of arachidonic to docosahexaenoic acid that were similar to those in the obligate heterozygotes. Freedman et al. do not report the degree of inflammation in the different types of samples, but since most of the patients with asthma were treated with corticosteroids, such treatment may have biased their results. Furthermore, since patients with asthma and other forms of allergy have repeatedly been reported to have an abnormal plasma fatty acid pattern,16 the findings of Freedman et al. in patients with cystic fibrosis need to be considered in the context of these other observations.
What do these findings mean for the treatment of patients with cystic fibrosis? The long-chain essential fatty acids and their eicosanoids have been shown to have a profound influence on membrane receptor function, transmembrane signaling mechanisms, phospholipase activation, calcium release, ion channels, and gene expression. Disturbances of this complex interactive system can have fundamental importance for cell function. In patients with cystic fibrosis, it seems reasonable to try to normalize plasma levels of essential fatty acids, although we know that the fatty acid profile of different tissues may not be reflected in the plasma, or even in the phospholipids of red-cell membranes. Until we understand the defective fatty acid metabolism in cystic fibrosis and how these abnormalities may interfere with CFTR function, specific treatment, especially with pharmacologic amounts of these acids, should be approached with great caution.
Source Information
From the Department of Pediatrics, Institute of the Health of Women and Children, G?teborg University, G?teborg, Sweden.
References
Farrell PM, Mischler EH, Engle MJ, Brown J, Lau S-M. Fatty acid abnormalities in cystic fibrosis. Pediatr Res 1985;19:104-109.
Strandvik B. Long chain fatty acid metabolism and essential fatty acid deficiency with special emphasis on cystic fibrosis. In: Bracco U, Decklelbaum RJ, eds. Polyunsaturated fatty acids in human nutrition. Vol. 28 of Nestlé Nutrition Workshop Series. New York: Raven Press, 1992:159-67.
Lai H-C, Kosorok MR, Laxova A, Davis LA, FitzSimmon SC, Farrell PM. Nutritional status of patients with cystic fibrosis with meconium ileus: a comparison with patients without meconium ileus and diagnosed early through neonatal screening. Pediatrics 2000;105:53-61.
Ulane MM, Butler JB, Peri A, Miele L, Ulane RE, Hubbard VS. Cystic fibrosis and phosphatidylcholine biosynthesis. Clin Chim Acta 1994;230:109-116.
Bhura-Bandali FN, Suh M, Man SFP, Clandinin MT. The F508 mutation in the cystic fibrosis transmembrane conductance regulator alters control of essential fatty acid utilization in epithelial cells. J Nutr 2000;130:2870-2875.
Carlstedt-Duke J, Br?nneg?rd M, Strandvik B. Pathological regulation of arachidonic acid release in cystic fibrosis: the putative basic defect. Proc Natl Acad Sci U S A 1986;83:9202-9206.
Levistre R, Lemnaouar M, Rybkine T, Béréziat G, Masliah J. Increase of bradykinin-stimulated arachidonic acid release in a delta F508 cystic fibrosis epithelial cell line. Biochim Biophys Acta 1993;1181:233-239.
Miele L, Cordella-Miele E, Xing M, Frizzell R, Mukherjee AB. Cystic fibrosis gene mutation (deltaF508) is associated with an intrinsic abnormality in Ca2+-induced arachidonic acid release by epithelial cells. DNA Cell Biol 1997;16:749-759.
Freedman SD, Blanco PG, Zaman MM, et al. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med 2004;350:560-569.
Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr 1999;70:Suppl:560S-569S.
Strandvik B, Gronowitz E, Enlund F, Martinsson T, Wahlstr?m J. Essential fatty acid deficiency in relation to genotype in patients with cystic fibrosis. J Pediatr 2001;139:650-655.
Underwood BA, Denning CR, Navab M. Polyunsaturated fatty acids and tocopherol levels in patients with cystic fibrosis. Ann N Y Acad Sci 1972;203:237-247.
Weber PC. The modification of the arachidonic acid cascade by n-3 fatty acids. Adv Prostaglandin Thromboxane Leukot Res 1990;20:232-240.
Strandvik B, Svensson E, Seyberth HW. Prostanoid biosynthesis in patients with cystic fibrosis. Prostaglandins Leukot Essent Fatty Acids 1996;55:419-425.
Corey EJ, Shih C, Cashman JR. Docosahexaenoic acid is a strong inhibitor of prostaglandin but not leukotriene biosynthesis. Proc Natl Acad Sci U S A 1983;80:3581-3584.
Yu G, Bj?rksten B. Polyunsaturated fatty acids in school children in relation to allergy and serum IgE levels. Pediatr Allergy Immunol 1998;9:133-138.(Birgitta Strandvik, M.D.,)