No indications for altered essential fatty acid metabolism in two murine models for cystic fibrosis

Abstract

A deficiency of essential fatty acids (EFA) is frequently described in cystic fibrosis (CF), but whether this is a primary consequence of altered EFA metabolism or a secondary phenomenon is unclear. It was suggested that defective long-chain polyunsaturated fatty acid (LCPUFA) synthesis contributes to the CF phenotype. To establish whether cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction affects LCPUFA synthesis, we quantified EFA metabolism in cftr ؊ / ؊ CAM and cftr ؉ / ؉ CAM mice. Effects of intestinal phenotype, diet, age, and genetic background on EFA status were evaluated in cftr ؊ / ؊ CAM mice, ⌬ F508/ ⌬ F508 mice, and littermate controls. EFA metabolism was measured by 13 C stable isotope methodology in vivo. EFA status was determined by gas chromatography in tissues of cftr ؊ / ؊ CAM mice, ⌬ F508/ ⌬ F508 mice, littermate controls, and C57Bl/6 wild types fed chow or liquid diet. After enteral administration of [ 13 C]EFA, arachidonic acid (AA) and docosahexaenoic acid (DHA) were equally 13 C-enriched in cftr ؊ / ؊ CAM and cftr ؉ / ؉ CAM mice, indicating similar EFA elongation/desaturation rates. LA, ALA, AA, and DHA concentrations were equal in pancreas, lung, and jejunum of chow-fed cftr ؊ / ؊ CAM and ⌬ F508/ ⌬ F508 mice and controls. LCPUFA levels were also equal in liquid diet-weaned cftr ؊ / ؊ CAM mice and littermate controls, but consistently higher than in age-and diet-matched C57Bl/6 wild types. We conclude that cftr ؊ / ؊ CAM mice adequately absorb and metabolize EFA, indicating that CFTR dysfunction does not impair LCPUFA synthesis. A membrane EFA imbalance is not inextricably linked to the CF genotype. EFA status in murine CF models is strongly determined by genetic background. -Werner, A., M. E. J. Bongers, M. J. Bijvelds, H. R. de Jonge, and H. J. Verkade. No indications for altered essential fatty acid metabolism in two murine models for cystic fibrosis.

Relation between Fatty Acid Composition and Clinical Status or Genotype in Cystic Fibrosis Patients

“…Not all CF animal models display the FA abnormalities however [11][12][13] . Strandvik et al [14] described an association of genotype severity with FA disturbances in CF patients.…”

“…The biochemical aberrations as well as morphological abnormalities were corrected by pharmacological doses of docosahexaenoic acid (DHA, 22: 6 -3). However, different CF mice models do not display the same FA abnormalities [12,13] . This could be a result of differences in functional CFTR protein, since Strandvik et al [14] described a relation between some severe mutations and FA abnormalities.…”

Persistence of Essential Fatty Acid Deficiency in Cystic Fibrosis Despite Nutritional Therapy

“…This profile is different from that usually present in typical nutritional EFA deficiency (9). Fatty acid composition may be influenced by genetic factors as shown in murine models (10,11) or in humans (12). The role played by pancreatic insufficiency may also be especially relevant because fat malabsorption persists in many patients despite pancreatic enzyme replacement (13).…”

Cholesterol feeding strongly reduces hepatic VLDL-triglyceride production in mice lacking the liver X receptor α

“…Hepatic lipid extracts were fractionated into PLs, CEs, TGs, and free fatty acids using TLC (20 3 20 cm, Silica gel 60 F254; Merck), and relative fatty acid composition in these fractions was determined by gas chromatography after methylation (16).…”