Ufmylation on UFBP1 alleviates non-alcoholic fatty liver disease by modulating hepatic endoplasmic reticulum stress

Abstract

Abstract Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease characterized by lipid accumulation and endoplasmic reticulum (ER) stress, while effective therapies targeting NAFLD characteristics are limited. Ufmylation is a newly found post-translational modification in which the Ubiquitin-fold modifier 1 (UFM1) protein is attached to its substrate via ufmylation modification system components. Ufmylation has been proposed to regulate ER stress via modifying UFM1 binding protein 1 (UFBP1), suggesting a potential role for ufmylation in the pathogenesis of NAFLD. However, the role of ufmylation in NAFLD is unknown. Herein, we aimed to reveal the role of ufmylation on UFBP1 in NAFLD and explore the underlying mechanisms. We observed an up-regulated expression of UFM1-conjugated proteins and ufmylation modification system components in livers with steatosis derived from NAFLD patients and NAFLD models, which was an adaptive response to the hepatic ER stress in NAFLD. In vitro, knocking down UFBP1 promoted lipid accumulation and lipogenesis in hepatocytes treated with free fatty acids (FFA), which could be rescued by re-expressing exogenous wild type UFBP1 (WT UFBP1) but not an UFBP1 mutant deficient in main ufmylation site lys267 (UFBP1 K267R). In vivo, ufmylation on UFBP1 ameliorated obesity, hepatic steatosis, hepatic lipogenesis, dyslipidemia, insulin resistance and liver damage in high fat diet (HFD)-induced NAFLD mice. We also demonstrated that knocking down UFBP1 promoted ER stress while re-expressing or overexpressing UFBP1 relieved ER stress in an ufmylation-dependent manner in NAFLD, which could be the underlying mechanism that led to the relief of abnormal hepatic lipogenesis and insulin resistance. Our data reveal a protective role of ufmylation on UFBP1 against NAFLD and offer a specific target for NAFLD treatment.