title: Lecithin:cholesterol acyltransferase deficiency protects against cholesterol-induced hepatic endoplasmic reticulum stress in mice.
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.
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, Department of Medicine, St. Michael's Hospital, Toronto M5B 1W8, Canada.
authors.forename: Lauren
authors.initials: L
authors.lastname: Hager
authors.forename: Lixin
authors.initials: L
authors.lastname: Li
authors.forename: Henry
authors.initials: H
authors.lastname: Pun
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Hossain
authors.forename: Graham F
authors.initials: GF
authors.lastname: Maguire
authors.forename: Mark
authors.initials: M
authors.lastname: Naples
authors.forename: Chris
authors.initials: C
authors.lastname: Baker
authors.forename: Lilia
authors.initials: L
authors.lastname: Magomedova
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tam
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cummins
authors.forename: Philip W
authors.initials: PW
authors.lastname: Connelly
authors.forename: Dominic S
authors.initials: DS
authors.lastname: Ng
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008074:Lipoproteins / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D002785:Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D000097587:Sterol O-Acyltransferase 2
chemical_list: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol; D004041:Dietary Fats; D008074:Lipoproteins; D026901:Membrane Transport Proteins; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D012333:RNA, Messenger; D011973:Receptors, LDL; D002785:Sterol O-Acyltransferase; D051782:Sterol Regulatory Element Binding Protein 2; D000097587:Sterol O-Acyltransferase 2; C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; C482445:Npc1l1 protein, mouse; C497391:Srebf2 protein, mouse