Fat absorption in cystic fibrosis mice is impeded by defective lipolysis and post-lipolytic events.
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.
Bijvelds
Marcel J C
MJ
Dept. of Biochemistry, Erasmus MC, Postbus 1738, NL-3000 DR Rotterdam, The Netherlands. m.bijvelds@erasmusmc.nl
Bronsveld
Inez
I
Havinga
Rick
R
Sinaasappel
Maarten
M
de Jonge
Hugo R
HR
Verkade
Henkjan J
HJ
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics; D004041:Dietary Fats / Q000378:metabolism*; D005223:Fats / Q000032:analysis; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005260:Female; D008066:Lipolysis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009154:Mutation; D046790:Pancreas, Exocrine / Q000378:metabolism; D014280:Triglycerides / Q000008:administration & dosage / Q000378:metabolism
D001647:Bile Acids and Salts; D004041:Dietary Fats; D005223:Fats; D005230:Fatty Acids, Nonesterified; D014280:Triglycerides; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator