Abstract

Post-prandial hypertriglyceridemia has emerged as a cardiovascular risk factor with limited therapeutic options. We have taken genetic and physiological approaches to identify and characertize novel factors that regulate intestinal lipid handling in the hope of revealing cellular pathways that dampen delivery of dietary lipids, opening the therapeutic window to blunting post-prandial lipid excursions. Liver X receptors (Lxrs) are master regulators of cholesterol catabolism, driving the elimination of cholesterol from the periphery to the lumen of the intestine. These nuclear hormone receptors are activated by oxysterol, ligands that accumulate when excess cholesterol is present. Loss of nr1h3 function causes anticipated gene regulatory changes and cholesterol intolerance, collectively reflecting high evolutionary conservation of zebrafish Lxra function. Intestinal nr1h3 activation delays transport of absorbed neutral lipids, with accumulation of neutral lipids in enterocyte cytoplasmic droplets, as visualized with histological stains, live fluorescent lipid probes, and ultrastructural analyses. This delay in transport of ingested neutral lipids protects animals over-expressing nr1h3 in the intestine from hypercholesterolemia and hepatic steatosis induced by a high-fat diet. On a gene regulatory level, Lxra induces expression of acsl3a , which encodes acyl-CoA synthetase long-chain family member 3a, a lipid droplet-anchored protein that directs fatty acyl chains into lipids. We have identified a gene regulatory network in enterocytes whereby the pace of delivery of dietary lipids is gated by Lxrs. Development of pharmacological agents to activate Lxrs has been hindered by synthetic Lxr agonists’ induction of hepatic lipogenesis and hypertriglyceridemia. The development of intestine-limited Lxr agonists could be of therapeutic value in blunting post-prandial hypertriglyceridemia.

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