ZFIN ID: ZDB-PUB-140718-6
Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids
Cruz-Garcia, L., Schlegel, A.
Date: 2014
Source: Journal of Lipid Research   55(9): 1944-58 (Journal)
Registered Authors: Schlegel, Amnon
Keywords: ACSL3, Diet and dietary lipids, Electron microscopy, Fatty acid/Transport, Intestine, Lipid droplets, Nuclear receptors/LXR, Nutrition, TALEN, zebrafish
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Biological Transport
  • Caco-2 Cells
  • Coenzyme A Ligases/genetics
  • Coenzyme A Ligases/metabolism
  • Diet, High-Fat/adverse effects
  • Enterocytes/metabolism*
  • Fatty Acids/metabolism
  • Fatty Liver/etiology
  • Fatty Liver/metabolism
  • Female
  • Gene Expression
  • Humans
  • Hypercholesterolemia/etiology
  • Hypercholesterolemia/metabolism
  • Intestinal Absorption
  • Lipid Droplets/metabolism*
  • Lipid Metabolism
  • Male
  • Molecular Sequence Data
  • Orphan Nuclear Receptors/physiology*
  • Zebrafish
PubMed: 25030662 Full text @ J. Lipid Res.
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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 massive hepatic de novo 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 severe cholesterol intolerance, collectively reflecting high evolutionary conservation of zebrafish Lxra function. In contrast, intestinal nr1h3 activation delays transport of absorbed neutral lipids, with accumulation of neutral lipids in enterocyte cytoplasmic droplets. Similarly, treatment of human enterocyte cells with an Lxr agonist induced increased lipid droplet formation. Cumulatively, this delay in transport of ingested neutral lipids protects animals from high fat diet-induced hypercholesterolemia and hepatic steatosis.
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