Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1861, Issue 9, Pages 1132-1141Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2016.06.014
Keywords
Cholesterol absorption; Chylomicron size; DGAT1 inhibition; Intestinal DGAT1 deficiency; Trans-intestinal cholesterol excretion
Funding
- Austrian Science Fund FWF [DK-MCD W1226, P27070, P22832, SFB-LIPOTOX F3004]
- Medical University of Graz
- Austrian Science Fund (FWF) [P22832, P27070] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [F 3004, P 27070, P 22832] Funding Source: researchfish
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Acyl-CoA:diacylglycerol acyltransferase I (DGAT1) is a key enzyme in triacylglycerol (TG) biosynthesis. Here we show that genetic deficiency and pharmacological inhibition of DGAT1 in mice alters cholesterol metabolism. Cholesterol absorption, as assessed by acute cholesterol uptake, was significantly decreased in the small intestine and liver upon DGATI deficiency/inhibition. Ablation of DGAT1 in the intestine (I-DGAT1(-/-)) alone is sufficient to cause these effects. Consequences of l-DGAT1 deficiency phenocopy findings in whole-body DGAT1(-/-) and DGAT1 inhibitor-treated mice. We show that deficiency/inhibition of DGAT1 affects cholesterol metabolism via reduced chylomicron size and increased trans-intestinal cholesterol excretion. These effects are independent of cholesterol uptake at the apical surface of enterocytes but mediated through altered dietary fatty acid metabolism. Our findings provide insight into a novel role of DGAT1 and identify a pathway by which intestinal DGAT1 deficiency affects whole-body cholesterol homeostasis in mice. Targeting intestinal DGAT1 may represent a novel approach for treating hypercholesterolemia. (C) 2016 The Authors. Published by Elsevier B.V.
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