F-box only protein 2 exacerbates non-alcoholic fatty liver disease by targeting the hydroxyl CoA dehydrogenase alpha subunit  

作　　者：Zhi Liu Ning-Yuan Chen Zhao Zhang Sai Zhou San-Yuan Hu 

机构地区：[1]Department of General Surgery,Qilu Hospital of Shandong University,Jinan 250012,Shandong Province,China [2]Department of General Surgery,Shandong Provincial Qian Foshan Hospital,Shandong University,Jinan 250014,Shandong Province,China [3]Department of General Surgery,Shandong First Medical University&Shandong Academy of Medical Sciences,Jinan 250117,Shandong Province,China

出　　处：《World Journal of Gastroenterology》2023年第28期4433-4450,共18页世界胃肠病学杂志（英文版）

基　　金：the National Natural Science Foundation of China,No.82070869 and 82270914.

摘　　要：BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a major health burden with an increasing global incidence.Unfortunately,the unavailability of knowledge underlying NAFLD pathogenesis inhibits effective preventive and therapeutic measures.AIM To explore the molecular mechanism of NAFLD.METHODS Whole genome sequencing(WGS)analysis was performed on liver tissues from patients with NAFLD(n=6)and patients with normal metabolic conditions(n=6)to identify the target genes.A NAFLD C57BL6/J mouse model induced by 16 wk of high-fat diet feeding and a hepatocyte-specific F-box only protein 2(FBXO2)overexpression mouse model were used for in vivo studies.Plasmid transfection,co-immunoprecipitation-based mass spectrometry assays,and ubiquitination in HepG2 cells and HEK293T cells were used for in vitro studies.RESULTS A total of 30982 genes were detected in WGS analysis,with 649 up-regulated and 178 down-regulated.Expression of FBXO2,an E3 ligase,was upregulated in the liver tissues of patients with NAFLD.Hepatocyte-specific FBXO2 overexpression facilitated NAFLD-associated phenotypes in mice.Overexpression of FBXO2 aggravated odium oleate(OA)-induced lipid accumulation in HepG2 cells,resulting in an abnormal expression of genes related to lipid metabolism,such as fatty acid synthase,peroxisome proliferator-activated receptor alpha,and so on.In contrast,knocking down FBXO2 in HepG2 cells significantly alleviated the OA-induced lipid accumulation and aberrant expression of lipid metabolism genes.The hydroxyl CoA dehydrogenase alpha subunit(HADHA),a protein involved in oxidative stress,was a target of FBXO2-mediated ubiquitination.FBXO2 directly bound to HADHA and facilitated its proteasomal degradation in HepG2 and HEK293T cells.Supplementation with HADHA alleviated lipid accumulation caused by FBXO2 overexpression in HepG2 cells.CONCLUSION FBXO2 exacerbates lipid accumulation by targeting HADHA and is a potential therapeutic target for NAFLD。

关 键 词：F-box only protein 2 Nonalcoholic fatty liver disease The hydroxyl CoA dehydrogenase alpha subunit Liver steatosis Ubiquitination Lipid accumulation 

分 类 号：R575.5[医药卫生—消化系统]