Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver disorders and accompanied by multiple metabolic dysfunctions. Although excessive lipid accumulation in hepatocytes has been identified as a crucial mediator of NAFLD development, the underlying mechanisms are very complicated and remain largely unknown. In this study, we reported that upregulated expression of the seven in absentia homolog 1 (Siah1) in the liver exacerbated NAFLD progression. Conversely, Siah1 downregulation markedly alleviated the high fat diet-induced accumulation of hepatic fat and expression of genes related to lipid metabolism in vitro and in vivo. The mechanistic study revealed that Siah1 interacted with sterol carrier protein 2 (Scp2) and promotes its ubiquitination and degradation, suggesting that Siah1 is an important activator of Scp2 ubiquitination in the context of NAFLD. Our results demonstrated that Siah1 regulated the lipid accumulation in NAFLD by interacting with Scp2. Thus, this study presents Siah1 as a promising therapeutic target in the development of NAFLD.
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