Lecithin:cholesterol acyltransferase deficiency protects against cholesterol-induced hepatic endoplasmic reticulum stress in mice

J Biol Chem. 2012 Jun 8;287(24):20755-68. doi: 10.1074/jbc.M112.340919. Epub 2012 Apr 12.

Abstract

We recently reported that lecithin:cholesterol acyltransferase (LCAT) knock-out mice, particularly in the LDL receptor knock-out background, are hypersensitive to insulin and resistant to high fat diet-induced insulin resistance (IR) and obesity. We demonstrated that chow-fed Ldlr-/-xLcat+/+ mice have elevated hepatic endoplasmic reticulum (ER) stress, which promotes IR, compared with wild-type controls, and this effect is normalized in Ldlr-/-xLcat-/- mice. In the present study, we tested the hypothesis that hepatic ER cholesterol metabolism differentially regulates ER stress using these models. We observed that the Ldlr-/-xLcat+/+ mice accumulate excess hepatic total and ER cholesterol primarily attributed to increased reuptake of biliary cholesterol as we observed reduced biliary cholesterol in conjunction with decreased hepatic Abcg5/g8 mRNA, increased Npc1l1 mRNA, and decreased Hmgr mRNA and nuclear SREBP2 protein. Intestinal NPC1L1 protein was induced. Expression of these genes was reversed in the Ldlr-/-xLcat-/- mice, accounting for the normalization of total and ER cholesterol and ER stress. Upon feeding a 2% high cholesterol diet (HCD), Ldlr-/-xLcat-/- mice accumulated a similar amount of total hepatic cholesterol compared with the Ldlr-/-xLcat+/+ mice, but the hepatic ER cholesterol levels remained low in conjunction with being protected from HCD-induced ER stress and IR. Hepatic ER stress correlates strongly with hepatic ER free cholesterol but poorly with hepatic tissue free cholesterol. The unexpectedly low ER cholesterol seen in HCD-fed Ldlr-/-xLcat-/- mice was attributable to a coordinated marked up-regulation of ACAT2 and suppressed SREBP2 processing. Thus, factors influencing the accumulation of ER cholesterol may be important for the development of hepatic insulin resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • ATP-Binding Cassette Transporters / biosynthesis
  • ATP-Binding Cassette Transporters / genetics
  • Animals
  • Cholesterol / genetics
  • Cholesterol / metabolism*
  • Dietary Fats / adverse effects
  • Dietary Fats / pharmacology
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / physiology
  • Endoplasmic Reticulum Stress*
  • Gene Expression Regulation / genetics
  • Insulin Resistance / genetics
  • Lecithin Cholesterol Acyltransferase Deficiency / genetics
  • Lecithin Cholesterol Acyltransferase Deficiency / metabolism*
  • Lecithin Cholesterol Acyltransferase Deficiency / pathology
  • Lipoproteins / biosynthesis
  • Lipoproteins / genetics
  • Liver / metabolism*
  • Liver / pathology
  • Membrane Transport Proteins / biosynthesis
  • Membrane Transport Proteins / genetics
  • Mice
  • Mice, Knockout
  • Phosphatidylcholine-Sterol O-Acyltransferase*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Sterol O-Acyltransferase / genetics
  • Sterol O-Acyltransferase / metabolism
  • Sterol Regulatory Element Binding Protein 2 / genetics
  • Sterol Regulatory Element Binding Protein 2 / metabolism

Substances

  • ABCG5 protein, mouse
  • ABCG8 protein, mouse
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • ATP-Binding Cassette Transporters
  • Dietary Fats
  • Lipoproteins
  • Membrane Transport Proteins
  • Npc1l1 protein, mouse
  • RNA, Messenger
  • Receptors, LDL
  • Srebf2 protein, mouse
  • Sterol Regulatory Element Binding Protein 2
  • Cholesterol
  • Sterol O-Acyltransferase
  • sterol O-acyltransferase 2
  • Phosphatidylcholine-Sterol O-Acyltransferase