title: Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids.
abstract: Liver X receptors (Lxrs) are master regulators of cholesterol catabolism, driving the elimination of cholesterol from the periphery to the lumen of the intestine. Development of pharmacological agents to activate Lxrs has been hindered by synthetic Lxr agonists' induction of hepatic lipogenesis and hypertriglyceridemia. Elucidating the function of Lxrs in regulating enterocyte lipid handling might identify novel aspects of lipid metabolism that are pharmacologically amenable. We took a genetic approach centered on the single Lxr gene nr1h3 in zebrafish to study the role of Lxr in enterocyte lipid metabolism. 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. This delay in transport of ingested neutral lipids protects animals 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. Forced overexpression of acls3a in enterocytes delays, in part, the appearance of neutral lipids in the vasculature of zebrafish larvae. Activation of Lxr in the intestine cell-autonomously regulates the rate of delivery of absorbed lipids by inducting a temporary lipid intestinal droplet storage depot.
authors.affiliation: University of Utah Molecular Medicine (U2M2) Program,University of Utah, Salt Lake City, UT 84112 Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes,University of Utah, Salt Lake City, UT 84112.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Cruz-Garcia
authors.affiliation: University of Utah Molecular Medicine (U2M2) Program,University of Utah, Salt Lake City, UT 84112 Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes,University of Utah, Salt Lake City, UT 84112 Department of Biochemistry, School of Medicine, University of Utah, Salt Lake City, UT 84112.
authors.forename: Amnon
authors.initials: A
authors.lastname: Schlegel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport; D018938:Caco-2 Cells; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D020895:Enterocytes / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D006937:Hypercholesterolemia / Q000209:etiology / Q000378:metabolism; D007408:Intestinal Absorption; D066292:Lipid Droplets / Q000378:metabolism*; D050356:Lipid Metabolism; D000071518:Liver X Receptors; D008297:Male; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors / Q000502:physiology*; D015027:Zebrafish; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D005227:Fatty Acids; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
keywords: acyl-CoA synthetase long-chain family member 3; diet and dietary lipids; electron microscopy; fatty acid/transport; intestine; nuclear receptors/liver X receptor; nutrition; transcription activator-like effector nuclease; zebrafish