Cellular cholesterol accumulation modulates high fat high sucrose (HFHS) diet-induced ER stress and hepatic inflammasome activation in the development of non-alcoholic steatohepatitis

被引：34

作者：

Bashiri, Amir ^{[1
,2
]}

Nesan, Dinushan ^{[1
]}

Tavallaee, Ghazaleh ^{[1
]}

Sue-Chue-Lam, Ian ^{[1
]}

Chien, Kevin ^{[1
]}

Maguire, Graham F. ^{[1
]}

Naples, Mark ^{[5
]}

Zhang, Jing ^{[5
]}

Magomedova, Lilia ^{[4
]}

Adeli, Khosrow ^{[5
]}

Cummins, Carolyn L. ^{[4
]}

Ng, Dominic S. ^{[1
,2
,3
]}

机构：

[1] St Michaels Hosp, Dept Med, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto, ON M5B 1W8, Canada

[2] Univ Toronto, Fac Med, Dept Physiol, Toronto, ON M5S 1A8, Canada

[3] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[4] Univ Toronto, Fac Pharm, Toronto, ON, Canada

[5] Hosp Sick Children, Res Inst, Mol Struct & Funct Program, 555 Univ Ave, Toronto, ON M5G 1X8, Canada

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS | 2016年 / 1861卷 / 07期

基金：

加拿大健康研究院;

关键词：

NASH; ER cholesterol; ER stress; Inflammasome; Cholesterol crystal; LCAT knockout mice; ENDOPLASMIC-RETICULUM STRESS; LECITHIN/CHOLESTEROL ACYLTRANSFERASE; STEATOSIS; ACID; HOMEOSTASIS; REDUCTASE; INSIGHTS; OBESITY;

D O I：

10.1016/j.bbalip.2016.04.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Non-alcoholic steatohepatitis (NASH), is the form of non-alcoholic fatty liver disease posing risk to progress into serious long term complications. Human and pre-clinical models implicate cellular cholesterol dysregulation playing important role in its development Mouse model studies suggest synergism between dietary cholesterol and fat in contributing to NASH but the mechanisms remain poorly understood. Our laboratory previously reported the primary importance of hepatic endoplasmic reticulum cholesterol (ER-Chol) in regulating hepatic ER stress by comparing the responses of wild type, Ldlr-/-xLcat+/+ and Ldlr-/-xLcat-/- mice, to a 2% high cholesterol diet (HCD). Here we further investigated the roles of ER-Chol and ER stress in HFHS diet induced NASH using the same strains. With HFHS diet feeding, both WT and Ldlr-/-xLcat+/+ accumulate ER-Chol in association with ER stress and inflammasome activation but the Ldlr-/-xLcat-/- mice are protected. By contrast, all three strains accumulate cholesterol crystal, in correlation with ER-Chol, albeit less so in Ldlr-/-xLcat-/- mice. By comparison, HCD feeding per se (i) is sufficient to promote steatosis and activate inflammasomes, and (ii) results in dramatic accumulation of cholesterol crystal which is linked to inflammasome activation in Ldlr-/-xLcat-/- mice, independent of ER-Chol. Our data suggest that both dietary fat and cholesterol each independently promote steatosis, cholesterol crystal accumulation and inflammasome activation through distinct but complementary pathways. In vitro studies using palmitateinduced hepatic steatosis in HepG2 cells confirm the key roles by cellular cholesterol in the induction of steatosis and inflammasome activations. These novel findings provide opportunities for exploring a cellular cholesterol focused strategy for treatment of NASH. (C) 2016 Elsevier B.V. All rights reserved.

引用

页码：594 / 605

页数：12

共 35 条

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