Abstract
LAG1 longevity assurance homolog 2 (LASS2), a highly conserved transmembrane protein, has been reported to be associated with nonalcoholic fatty liver disease (NAFLD). However, the effect of LASS2 on energy homeostasis and its mechanism remains unknown. In this study, we found lower expression levels of LASS2 in the livers of mice with liver steatosis induced by a high-fat diet (HFD) and free fatty acids (FFAs)-treated hepatocytes. In FFAs-treated Hepa1-6 cells and mouse primary hepatocytes (MPHs), LASS2 overexpression significantly decreased intracellular lipid content compared with the control cells. LASS2 overexpression also significantly upregulated lipolysis-related proteins, such as ATGL and HSL, and inhibited lipogenesis-related proteins, such as SREBP1 and FAS. In addition, the phosphorylation levels of AMPK and ACC increased significantly. On the contrary, LASS2 knockdown in FFAs-treated hepatocytes aggravated lipid accumulation via facilitating lipogenesis and inhibiting lipolysis. Further, co-IP and LC-MS analysis found that LASS2 might interacted with NDUFS2 to inhibit lipogenesis. The production of mitochondrial reactive oxygen species (mtROS) may be related to the interaction between LASS2 and NDUFS2. Collectively, we are the first time to showed that LASS2 might promote the phosphorylation of AMPK via mtROS produced by interaction with NDUFS2/OXPHOS, thus inhibiting lipogenesis.
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