Cholesterol Plays a Crucial Role in High-fat-diet Induced ER stress and Non-alcoholic Fatty Liver Disease

By comparing C57 mice with two dyslipidemic models, LDL-receptor null (LDLR-/-) and LCAT/LDL-receptor null mice (LCAT-/-xLDLR-/-), our lab showed an observation of ER-membrane cholesterol being necessary to modulate ER-stress in a high-cholesterol-diet feeding paradigm. Here, we hypothesized that hepatic cholesterol biosynthesis plays an important role in mediating high-fat-diet-induced hepatic ER stress and NAFLD. In vivo, we fed C57, LDLR-/-, LCAT-/-xLDLR-/- mice a high-fat-diet for 16 weeks. Markers for hepatic ER-stress, cholesterol biosynthesis, ER-cholesterol, NAFLD and inflammasome were measured. High-fat-diet feeding induced ER-stress, NAFLD, cholesterol biosynthesis, NLRP3 activation and ER-membrane cholesterol accumulation in both C57 and LDLR-/- mice, while LCAT-/-xLDLR-/- mice were protected. In vitro, HepG2 cells were treated with palmitate overnight with/without zaragozic acid (ZA), to inhibit cholesterol biosynthesis. Treatment with palmitate induced ER-stress, cholesterol biosynthesis and NLRP3 activation, which were abrogated by ZA treatment. These findings implicate the role of cholesterol in nutritional excess-induced hepatic metabolic complications.M.Sc.2016-11-19 00:00:0