Novel role of a triglyceride-synthesizing enzyme: DGAT1 at the crossroad between triglyceride and cholesterol metabolism

作者：Sachdev Vinay; Leopold Christina; Bauer Raimund; Patankar Jay V; Iqbal Jahangir; Obrowsky Sascha; Boverhof Renze; Doktorova Marcela; Scheicher Bernhard; Goeritzer Madeleine; Kolb Dagmar; Turnbull Andrew V; Zimmer Andreas; Hoefler Gerald; Hussain M Mahmood; Groen Albert K; Kratky Dagmar^*

来源：Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids, 2016, 1861(9): 1132-1141.

DOI：10.1016/j.bbalip.2016.06.014

• Cholesterol absorption
• Chylomicron size
• DGAT1 inhibition
• Intestinal DGAT1 deficiency
• Trans-intestinal cholesterol excretion

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.

• 出版日期2016-9