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MARCHF6-ERAD regulates hepatic lipid metabolism and MASLD development

ABSTRACT: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a growing global health concern. Increased de novo lipogenesis (DNL), largely mediated by Sterol Regulatory Element-Binding Protein 1 (SREBP1), is a hallmark of MASLD. However, the post-translational mechanisms regulating SREBP1 turnover remain poorly understood. The endoplasmic reticulum-associated degradation (ERAD) pathway ensures protein quality and quantity control, yet its role in hepatic lipid metabolism remains elusive. Here, we investigate the function of the ERAD-specific E3 ubiquitin ligase MARCHF6 in hepatic lipid homeostasis and MASLD pathogenesis.We found hepatic MARCHF6 expression was significantly reduced in both MASLD mouse models and human patients. Liver-specific Marchf6 deletion aggravated hepatic lipid accumulation, fibrosis, and inflammation. Transcriptomic and proteomic analyses revealed upregulation of lipogenic genes in Marchf6Alb livers, with a marked increase in SREBP1 protein levels. Mechanistically, MARCHF6 directly interacted with and ubiquitinated SREBP1, targeting it for proteasomal degradation. Loss of MARCHF6 prolonged SREBP1 half-life, driving excessive DNL.

ORGANISM(S): Mus musculus

PROVIDER: GSE319144 | GEO | 2026/05/28

REPOSITORIES: GEO

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