The E3 ubiquitin-protein ligase Trim31 alleviates non-alcoholic fatty liver disease by targeting Rhbdf2 in mouse hepatocytes

Abstract

Systemic metabolic syndrome significantly increases the risk of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). However, no effective therapeutic strategies are available, practically because our understanding of its complicated pathogenesis is poor. Here we identify the tripartite motif-containing protein 31 (Trim31) as an endogenous inhibitor of rhomboid 5 homolog 2 (Rhbdf2), and we further determine that Trim31 directly binds to Rhbdf2 and facilitates its proteasomal degradation. Hepatocyte-specific Trim31 ablation facilitates NAFLD-associated phenotypes in mice. Inversely, transgenic or ex vivo gene therapy-mediated Trim31 gain-of-function in mice with NAFLD phenotypes virtually alleviates severe deterioration and progression of steatohepatitis. The current findings suggest that Trim31 is an endogenous inhibitor of Rhbdf2 and downstream cascades in the pathogenic process of steatohepatitis and that it may serve as a feasible therapeutical target for the treatment of NAFLD/NASH and associated metabolic disorders.

Studies on Bioactive Components of Red Ginseng by UHPLC-MS and Its Effect on Lipid Metabolism of Type 2 Diabetes Mellitus

“…The experiments showed that the number of lipid droplets in HepG2 cells treated with 25, 50, and 100 μg/ml RGW decreased significantly, indicating that one of the reasons for the improvement in steatosis of hepatocytes may be a reduction in lipid deposition. Likewise, a study demonstrated that the reduction of hepatic steatosis leads to the recovery of liver function and the call-back of parameters related to lipid metabolism ( 35 ), which also confirmed our previous experimental results.…”

Hepatocyte phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK

“…Developing effective strategies for NASH management largely relies on the target of the key regulators in its pathogenic pathways. Recent studies on the interaction between genetic and environmental factors on fatty liver show that metabolic disorders can significantly amplify the effects of gene variants on NASH, from steatosis to hepatic inflammation and cirrhosis 11 , 12 , 14 , 15 . Preliminary clinical trials have indicated that NASH patients with specific gene variants respond differently to lifestyle and drug intervention 44 .…”

“…Herein, more studies on the treatment of NASH in specific gene variants are urgently required, which may be helpful to guide personalized treatment in the near future. Emerging studies have reported that gene therapy approaches are of potential for the treatments of hepatic steatosis and its related HCC 10 – 15 , 45 , 46 .…”

“…Ex vivo gene therapy involves the genetic modification of cells outside of the body to produce therapeutic factors and their subsequent transplantation back into patients or recipient animals 13 , 14 . We recently reported that ex vivo gene therapy-mediated Trim31 gain-of-function virtually alleviates severe deterioration and progression of steatohepatitis in mice with NAFLD phenotypes 15 . Therefore, a better understanding of NASH pathogenesis and identifying the key therapeutic targets are urgently required.…”

The E3 ligase TRIM31 regulates hematopoietic stem cell homeostasis and MLL-AF9 leukemia

“…TRIM31 not only contributes significantly to cerebral ischemic injury by promoting degradation of TIGAR 14 , but also contributes in hypertensive nephropathy by promoting degradation of MAP3K7 15 . Through targeting Rhbdf2 in mouse hepatocytes, TRIM31 also alleviates non-alcoholic fatty liver disease 16 .…”