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Lecithin:Cholesterol Acyltransferase Deficiency Protects against Cholesterol-induced Hepatic Endoplasmic Reticulum Stress in Mice

Our laboratory has recently reported that lecithin:cholesterol acyltransferase (LCAT) deficient mice are hypersensitive to insulin and resistant to diet-induced obesity, particularly in the LDL receptor (LDLR) knockout background. These phenotypes are linked to hepatic endoplasmic reticulum (ER) stress, which we showed is elevated basally and highly inducible in LDLR deficient mice. While in LCAT/LDLR deficient mice, ER stress is normalized basally and its diet-induction is attenuated. Mechanistically, we show here that excess free cholesterol (FC), in part from the bile, accumulates in the ER membrane of LDLR deficient mice. In contrast, LCAT/LDLR deficient mice have reduced levels of ER membrane FC and are resistant to cholesterol diet-induced elevations, in part from increased INSIG-1 expression and cholesterol esterification by ACAT2. Our analysis has led to the first report of cholesterol-induced hepatic ER stress in vivo and the identification of ER FC levels as a critical indicator of ER stress susceptibility.

Identiferoai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/30620
Date08 December 2011
CreatorsHager, Lauren
ContributorsNg, Dominic
Source SetsUniversity of Toronto
Languageen_ca
Detected LanguageEnglish
TypeThesis

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