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

Abstract

Background: Hepatic ER stress promotes insulin resistance, but the role of cholesterol in this pathway is unknown. Results: LCAT-deficient mice maintain a low ER cholesterol and are protected from cholesterol-induced ER stress. Conclusion: ER cholesterol, not tissue cholesterol, is crucial for hepatic ER stress development. Significance: Modulators of hepatic ER cholesterol may be novel targets to treat diabetes.

Distinct metabolic and vascular effects of dietary triglycerides and cholesterol in atherosclerotic and diabetic mouse models

“…Groups not sharing the same letter are considered statistically different when comparing effects of both diet ϫ genotype among the different groups. tance even in the face of a low-fat diet (9,26). This is especially important considering that the LDLr Ϫ/Ϫ is a model often used in metabolic studies.…”

Lecithin:Cholesterol Acyltransferase (LCAT) Deficiency Promotes Differentiation of Satellite Cells to Brown Adipocytes in a Cholesterol-dependent Manner

“…We detected ectopic BAT islands located in the interfiber regions of the skeletal muscle of adult Ldlr Ϫ/Ϫ xLcat Ϫ/Ϫ (DKO) mice (12) in association with a metabolically protected phenotype showing resistance to dietinduced obesity and glucose intolerance as well as increased energy expenditure, the latter finding being based on indirect calorimetry, when compared with their Ldlr Ϫ/Ϫ xLcat ϩ/ϩ (SKO) controls (12,13). LCAT is the enzyme that hydrolyzes phosphatidylcholine at the sn-2 position and transfers the fatty acid to convert free cholesterol into esterified cholesterol in circulating lipoproteins.…”

“…LCAT-deficient mice develop selective alterations in tissue lipids, including lowered cholesterol and lipid composition in the adrenals and the liver (12,16,17). Some of these changes are linked to protective phenotypes because our laboratory has shown recently that DKO mice protected from hepatic ER cholesterol accumulation are also protected from hepatic ER stress and insulin resistance (13).…”

“…, and Lcat Ϫ/Ϫ (LCAT-KO) mice in C57Bl/6 background were generated as described previously (13,17). C57BL/6 wild type (WT) mice were used as controls.…”

“…C57BL/6 wild type (WT) mice were used as controls. Only age-matched female animals were used in all experiments to minimize previously reported gender-dependent effects (13). Animals were bred and monitored at the Li Ka Shing Knowledge Institute Research Vivarium, and all experimental procedures used were according to protocols approved by the Animal Care Committee.…”