LASS2通过诱导mtROS激活自噬抑制胆固醇合成改善非酒精性脂肪肝脂代谢紊乱OA

Objective To determine the role of longevity assurance homolog 2(LASS2)overexpression or knock-down in non-alcoholic fatty liver disease(NAFLD)and to explore the underlying molecular mechanisms.Methods NAFLD was induced in C57BL/6J mice by feeding a high-fat diet(HFD).Mouse primary hepatocytes(MPHs)were treated with free fatty acids(FFAs)to establish steatosis,LASS2 was overexpressed or knocked down both in vivo and in vitro using adenovirus vectors.Liver weight,hepatic fat content,and serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),triglycerides(TG),total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),and low-density lipoprotein cholesterol(LDL-C),as well as hepatic TG and TC levels were measured in each group.Western blot was used to detect protein levels related to cholesterol metabolism and the autophagic pathway.Imaging of live cells labelled with the MitoSOXTM Red probe to detect levels of mitochondrial reactive oxygen species(mtROS).Results Compared with controls,HFD-fed mice showed significant increases in liver weight,and serum levels of ALT,AST,TG,TC,HDL-C,and LDL-C,as well as hepatic TG and TC levels(P＜0.05).Overexpression of LASS2 markedly reduced all these parameters(P＜0.05).RT-qPCR and Western blot revealed that LASS2 overexpression strongly sup-pressed SREBP2 and HMGCR at both mRNA and protein levels(P＜0.05).Live-cell imaging showed that LASS2 overexpression increased mtROS production(P＜0.05).Western blot further demonstrated that LASS2 overexpression raised the LC3-Ⅱ/LC3-Ⅰ ratio and the protein levels of Beclin-1,ATG3,ATG5,and ATG7,while decreasing p62 expression(P＜0.05).Knockdown of LASS2 produced the opposite effects.Conclusion LASS2 may activate autophagy by promoting mtROS production,thereby suppressing cholesterol synthesis and improving lipid metabolism disorders.These findings suggest LASS2 as a potential new therapeutic target for NAFLD.