M.J.C. Bijvelds , H.J. Verkade , M. Sinaasappel , H.R. De Jonge
Department of Biochemistry Erasmus MC, Rotterdam, Netherlands, Department of Pediatric Gastroenterology Erasmus MC, Rotterdam, Netherlands, Department of Pediatrics Academic Hospital Groningen, Groningen, Netherlands
Background & Aims: Fat malabsorption in cystic fibrosis (CF) patients is only partially corrected by lipase supplementation, indicating that factors other than lipase shortage limit fat absorption. We searched for such modulators of fat absorption in CF mice.
Methods: Fecal fat and bile salt excretion, lipolysis, fatty acid absorption, and biliary and pancreatic secretion were assessed in homozygous DF508 mice and cftr null mice.
Results: Both CF models showed enhanced fecal bile salt excretion, but bile flow and total biliary bile salt output were unaffected. Fat excretion was increased only in null mice. Although fat excretion was not enhanced in DF508 mice, the rate of plasma triglyceride accumulation after olive oil gavage was reduced to a similar extent as in null mice. However, lipolytic capacity, assessed by measuring triolein-derived lipid absorption relative to oleate uptake, was reduced only in null mice. Lipase activity, chloride levels, and pH values of pancreatic secretions were unaffected. Lipolytic activity was partially restored by suppression of gastric acid.
Conclusions: As pancreatic and biliary secretion are not impaired in these CF mice, defective fat absorption could be studied in the absence of lipase or bile salt deficiency. Absorption of fatty acids is delayed in both DF508 mice and null mice, but only in the latter does protracted fatty acid uptake concur with defective lipolysis, leading to high fat loss.
To our knowledge, this is the first study documenting distinct effects of the CF condition (null mice vs. DF508 mutants) on fat handling. Our data suggest that incomplete neutralization of gastric acid plays a key role in fat malabsorption.