Hepatic Alarmins and Mitochondrial Dysfunction under Residual Hyperlipidemic Stress Lead to Irreversible NAFLD  

作　　者：Luminita Ivan Elena Uyy Viorel I.Suica Raluca M.Boteanu Aurel Cerveanu-Hogas Rune Hansen Felicia Antohe 

机构地区：[1]Department of Proteomics,Institute of Cellular Biology and Pathology“Nicolae Simionescu”of the Romanian Academy,Bucharest,Romania [2]Department of Health Research,SINTEF Digital,Trondheim,Norway [3]Department of Circulation and Medical Imaging,Norwegian University of Science and Technology,Trondheim,Norway

出　　处：《Journal of Clinical and Translational Hepatology》2023年第2期284-294,共11页临床与转化肝病杂志（英文版）

基　　金：supported by the Romanian Academy and in part by a grant from the Romanian National Authority for Scientific Research and Innovation,CCCDI-UEFISCDI project COFUND-ERA-CVD-XploreCAD,No.41/2018 within PNCDI III.

摘　　要：Background and Aims:Nonalcoholic fatty liver disease(NAFLD)includes a range of progressive disorders generated by excess lipid accumulation in the liver leading to hepatic steatosis and eventually fibrosis.We aimed to identify by high performance mass spectrometry-based proteomics the main signaling pathways and liver proteome changes induced by hypercholesterolemia in a rabbit atherosclerotic model that induced high accumulation of lipids in the liver.Methods:The effect of combined lipid-lowering drugs(statins and anti-PCSK9 monoclonal antibody)were used after the interruption of the hypercholesterolemic diet to identify also the potential mediators,such as alarmins,responsible for the irreversible NAFLD build up under the hyperlipidemic sustained stress.Results:Proteomic analysis revealed a number of proteins whose abundance was altered.They were components of metabolic pathways including fatty-acid degradation,glycolysis/gluconeogenesis,and nonalcoholic fatty liver disease.Mitochondrial dysfunction indicated alteration at the mitochondrial respiratory chain level and down-regulation of NADH:ubiquinone oxidoreductase.The expression of a majority of cytochromes(P4502E1,b5,and c)were up-regulated by lipid-lowering treatment.Long-term hyperlipidemic stress,even with a low-fat diet and lipid-lowering treatment,was accompanied by alarmin release(annexins,galectins,HSPs,HMGB1,S100 proteins,calreticulin,and fibronectin)that generated local inflammation and induced liver steatosis and aggressive fibrosis(by high abundance of galectin 3,fibronectin,and calreticulin).Conclusions:The novel findings of this study were related to the residual effects of hyperlipidemic stress with consistent,combined lipid-lowering treatment with statin and inhibitor of PCSK9.

关 键 词：Nonalcoholic fatty liver disease ATHEROSCLEROSIS PROTEOMIC ALARMINS FIBROSIS 

分 类 号：R575.5[医药卫生—消化系统]