The fatty acid imbalance of cystic fibrosis exists at birth independent of feeding in pig and ferret models

Abstract

Persons with cystic fibrosis (CF) exhibit a unique alteration of fatty acid composition, marked especially among polyunsaturates by relative deficiency of linoleic acid and excess of Mead acid. Relative deficiency of docosahexaenoic acid is variably found. However, the initial development of these abnormalities is not understood. We examined fatty acid composition in young CF ferrets and pigs, finding abnormalities from the day of birth onward including relative deficiency of linoleic acid in both species. Fatty acid composition abnormalities were present in both liver and serum phospholipids of newborn CF piglets even prior to feeding, including reduced linoleic acid and increased Mead acid. Serum fatty acid composition evolved over the first weeks of life in both non-CF and CF ferrets, though differences between CF and non-CF persisted. Although red blood cell phospholipid fatty acid composition was normal in newborn animals, it became perturbed in juvenile CF ferrets including relative deficiencies of linoleic and docosahexaenoic acids and excess of Mead acid. In summary, fatty acid composition abnormalities in CF pigs and ferrets exist from a young age including at birth independent of feeding and overlap extensively with the abnormalities found in humans with CF. That the abnormalities exist prior to feeding implies that dietary measures alone will not address the mechanisms of imbalance.

Arteriovenous metabolomics in pigs reveals CFTR regulation of metabolism in multiple organs

“…Our results indicate marked abnormalities in lung LCFA uptake by CFTR loss. Previous studies reported altered LCFA levels in people with CF; linoleic acid (C18:2), eicosatrienoic acid (C20:3), docosahexaenoic acid (C22:6), and arachidonic acid (C20:4) are the LCFAs most often cited ( 43 , 65 – 70 ). However, dietary fat malabsorption due to pancreatic failure and altered intestinal function cloud interpretation in human studies.…”

Changes in Essential Fatty Acids and Ileal Genes Associated with Metabolizing Enzymes and Fatty Acid Transporters in Rodent Models of Cystic Fibrosis

“…In CF mice, some models also fail to demonstrate a reduction in LA in the serum [ 21 ], while other CF mouse models do exhibit a reduction [ 14 , 22 ]. A recent manuscript identified a reduction in LA in CF pigs and CF ferrets [ 23 ]. This suggests a species-specific and age-specific changes in LA in animal models of CF.…”

“…The requirement of LA in the diet is ~1.5% [ 24 ], with rats in this study consuming ~3% [ 16 ]. It has been shown in vitro that elevated LA in the culture media increases lung epithelial cell LA concentrations [ 23 , 25 ]; therefore, elevated LA in the diet may increase the concentrations in serum. Notably, the rats in this study were non-fasted, with samples collected in the light cycle, where rodents graze less.…”

Special Issue: “Recent Advances in Ion Channels and Ion Channelopathies”

“…Understanding the ileal genetic changes in essential fatty acid metabolic pathways in the rat model (contribution 5), may provide us with a better understanding about the pathological changes associated with CF in non-lung tissue. Interestingly, a study in the CF pig demonstrated that the essential fatty acid changes are not due to diet, as these changes exist at birth [17]. Thus, in addition to changes in cell signal transduction and transport, ion channel dysfunction may lead to imbalances in lipid metabolism.…”