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

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 the specific characteristics of NAFLD are limited. Ufmylation is a newly found post-translational modification process that involves the attachment of the Ubiquitin-fold modifier 1 (UFM1) protein to its substrates via ufmylation modification system. Ufmylation regulates ER stress via modifying UFM1 binding protein 1 (UFBP1), suggesting a potential role for ufmylation in NAFLD pathogenesis. However, the precise role of ufmylation in NAFLD remains unclear. Herein, we aim to elucidate the impact of ufmylation on UFBP1 in NAFLD and explore the underlying mechanisms involved. We observed increased expression of UFM1-conjugated proteins and ufmylation modification system components in livers with steatosis derived from NAFLD patients and NAFLD models. Upregulation of ufmylation on hepatic proteins appeared to be an adaptive response to hepatic ER stress in NAFLD. In vitro, knocking down UFBP1 resulted in increased lipid accumulation and lipogenesis in hepatocytes treated with free fatty acids (FFA), which could be rescued by wild-type UFBP1 (WT UFBP1) but not by a mutant form of UFBP1 lacking the main ufmylation site lys267 (UFBP1 K267R). In vivo, ufmylation on UFBP1 ameliorated obesity, hepatic steatosis, hepatic lipogenesis, dyslipidemia, insulin resistance and liver damage in mice with NAFLD induced by a high fat diet (HFD). We also demonstrated that the downregulation of UFBP1 induced ER stress, whereas the reintroduction or overexpression of UFBP1 alleviated ER stress in a manner dependent on ufmylation in NAFLD. This mechanism could be responsible for the amelioration of aberrant hepatic lipogenesis and insulin resistance in NAFLD. Our data reveal a protective role of ufmylation on UFBP1 against NAFLD and offer a specific target for NAFLD treatment.

Endoplasmic reticulum stress: bridging inflammation and obesity-associated adipose tissue

“…Phosphorylated IRE1α can induce the expression of XBP1s and caspase-2, leading to liver steatosis, hepatocyte damage, and insulin resistance (IR). Similarly, phosphorylated PERK induces the phosphorylation of eIF2α and the expression of ATF4, further promoting the pathological process of liver steatosis ( 125 ). Currently, the treatment for NAFLD is based on dietary control, physical activity, and surgical weight loss, but the UPR has recently been proven to be an ideal target for various drugs aimed at alleviating the progression of NAFLD.…”

DDRGK1-mediated ER-phagy attenuates acute kidney injury through ER-stress and apoptosis

“…In ketosis-induced cow liver injury, there’s a reduction in DDRGK1-dependent UFMylation, accompanied by a decrease in UFM1 [ 39 ]. Similarly, in nonalcoholic fatty liver disease in mice, there’s an upregulation of DDRGK1, UFM1, and UFM1-conjugated DDRGK1, contributing to increased UFMylation expression [ 40 ]. Our study further corroborates these findings, showing a reduction in DDRGK1, UFL1, and UFM1 in acute kidney injury, which suggests a decrease in ER-phagy.…”

Examining the Pathogenesis of MAFLD and the Medicinal Properties of Natural Products from a Metabolic Perspective

“…The endoplasmic reticulum, as a membrane organelle rich in lipid components, is significantly affected by lipotoxicity. Large amounts of toxic lipids initiate the unfolded protein response pathway through endoplasmic reticulum stress, which in turn leads to MAFLD via upregulating the DNL pathway, activating inflammasomes, and inducing hepatocyte apoptosis [84][85][86]. The inhibition of over-activated endoplasmic reticulum stress in hepatocytes represents a novel therapeutic strategy for MAFLD [87].…”