Fat absorption in cystic fibrosis mice is impeded by defective lipolysis and post-lipolytic events

Abstract

Cystic fibrosis (CF) is frequently associated with progressive loss of exocrine pancreas function, leading to incomplete digestion and absorption of dietary fat. Supplementing patients with pancreatic lipase reduces fat excretion, but it does not completely correct fat malabsorption, indicating that additional pathological processes affect lipolysis and/or uptake of lipolytic products. To delineate the role of such (post) lipolytic processes in CF-related fat malabsorption, we assessed fat absorption, lipolysis, and fatty acid uptake in two murine CF models by measuring fecal fat excretion and uptake of oleate- and triolein-derived lipid. Pancreatic and biliary function was investigated by determining lipase secretion and biliary bile salt (BS) secretion, respectively. A marked increase in fecal fat excretion was observed in cftr null mice but not in homozygous DeltaF508 mice. Fecal BS loss was enhanced in both CF models, but biliary BS secretion rates were similar. Uptake of free fatty acid was delayed in both CF models, but only in null mice was a specific reduction in lipolytic activity apparent, characterized by strongly reduced triglyceride absorption. Impaired lipolysis was not due to reduced pancreatic lipase secretion. Suppression of gastric acid secretion partially restored lipolytic activity and lipid uptake, indicating that incomplete neutralization of gastric acid impedes fat absorption. We conclude that fat malabsorption in cftr null mice is caused by impairment of lipolysis, which may result from aberrant duodenal pH regulation.

IGF Binding Protein-3 Treatment Alters Intestinal Cell Proliferation But Not Body Weight of Adult Cystic Fibrosis Transmembrane Conductance Regulator Deficient Mice

“…The low levels of serum albumin and triglycerides in the CF mice of this study indicates a compromised nutrition level and reduced lipid absorption (20), both of which were ameliorated by rhIGFBP-3 treatment. A positive association between increased IGFBP-3 levels and each of serum triglycerides (34) and albumin levels (35) has been reported, but a causal mechanism linking these measures, if such exists, is unknown.…”

“…As an assessment of the nourishment level in these mice serum albumin was assayed and as previous studies report lower serum triglycerides in CF mice (4,20), we determined whether the treatment affected this phenotype. The serum levels of albumin and triglycerides were found to be lower in CF compared with WT mice (p ϭ 0.0007 and p ϭ 0.02, respectively) and to increase by administration of rhIGFBP-3 in CF mice (p ϭ 0.03 and p ϭ 0.015, respectively; Fig.…”

Mouse as a Model of Growth Retardation in Cystic Fibrosis

“…CF mice have severe gastrointestinal disease (16,17) and CF mice with a null Cftr mutation have lipid malabsorption (36). We speculate that loss of Cftr function results in intestinal epithelial cell dysfunction, including altered fluid and electrolyte transport, but also malabsorption in this tissue.…”

“…To quantify this phenomenon, an important area of future research would be to measure total fecal energy losses in CF mice. Since the CF mouse has minor pancreatic disease (16,36), this experiment would help elucidate the role of primary intestinal disease on malabsorption and growth.…”

Ursodeoxycholic Acid Ameliorates Intrahepatic Cholestasis Independent of Biliary Bicarbonate Secretion in <i>Vil2^kd</i>^/<i>^kd</i> Mice

“…Bijvelds et al also revealed that cftr null mice showed similar increased fat excretion and fecal bile salt loss. 24) Similar to that observed in the bile ducts, functional defects in CFTR might occur in the intestine. This may lead to intestinal malabsorption of bile acids in Vil2 kd/kd mice, as has been reported in cystic fibrosis (CF) patients.…”