Homocysteine promotes hepatic steatosis by activating the adipocyte lipolysis in a HIF1α-ERO1α-dependent oxidative stress manner.

Hyperhomocysteinemia (HHcy) is related to liver diseases, such as nonalcoholic fatty liver (NAFL). Although the precise pathogenesis of NAFL is still largely unknown, the links between organs seem to play a vital role. The current study aimed to explore the role of white adipose tissue in homocysteine (Hcy)-induced NAFL. Blood samples from nonhyperhomocysteinemia or hyperhomocysteinemia individuals were collected to assess correlation between Hcy and triglyceride (TG) or free fatty acids (FFAs) levels. C57BL/6 mice were maintained on a high-methionine diet or administered with Hcy (1.8 g/L) in the drinking water to establish an HHcy mouse model. We demonstrated that Hcy activated adipocyte lipolysis and that this change was accompanied by an increased release of FFAs and glycerol. Excessive FFAs were taken up by hepatocyte, which resulted in lipid accumulation in the liver. Treatment with acipimox (0.08 g kg -1 day -1), a potent chemical inhibitor of lipolysis, markedly decreased Hcy-induced NAFL. Mechanistically, hypoxia-inducible factor 1α (HIF1α)-endoplasmic reticulum oxidoreductin 1α (ERO1α) mediated pathway promoted H2O2 accumulation and induced endoplasmic reticulum (ER) overoxidation, ER stress and more closed ER-lipid droplet interactions, which were responsible for activating the lipolytic response. In conclusion, this study reveals that Hcy activates adipocyte lipolysis and suggests the potential utility of targeted ER redox homeostasis for treating Hcy-induced NAFL.