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

Autor: Jing Zhang, Kevin Chien, Mark Naples, Dominic S. Ng, Dinushan Nesan, Graham F. Maguire, Amir Bashiri, Carolyn L. Cummins, Ian Sue-Chue-Lam, Khosrow Adeli, Ghazaleh Tavallaee, Lilia Magomedova
Rok vydání: 2016
Předmět:
0301 basic medicine
medicine.medical_specialty
Inflammasomes
Palmitic Acid
Biology
Diet
High-Fat
Cholesterol
Dietary
Phosphatidylcholine-Sterol O-Acyltransferase
Mice
03 medical and health sciences
chemistry.chemical_compound
Lecithin Cholesterol Acyltransferase Deficiency
Non-alcoholic Fatty Liver Disease
Internal medicine
medicine
Animals
Humans
Molecular Biology
Mice
Knockout
Cholesterol
Endoplasmic reticulum
Fatty liver
Wild type
Inflammasome
Hep G2 Cells
Cell Biology
Endoplasmic Reticulum Stress
Lipid Metabolism
medicine.disease
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Endocrinology
Gene Expression Regulation
Liver
Receptors
LDL
Biochemistry
chemistry
Unfolded protein response
Female
lipids (amino acids
peptides
and proteins)
Steatosis
Steatohepatitis
Oxidation-Reduction
Signal Transduction
medicine.drug
Zdroj: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1861:594-605
ISSN: 1388-1981
DOI: 10.1016/j.bbalip.2016.04.005
Popis: 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 palmitate-induced 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.
Databáze: OpenAIRE
Externí odkaz: