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.

MicroRNAs (miRNAs) as a class of small noncoding RNA molecules regulate the expression of targeted gene. The dysregulation of microRNAs is reported to be involved in carcinogenesis and tumor progression. Here, we identified miR-140-3p as a downregulated microRNA in most cancer tissues including lung cancer tissues, compared with their normal counterparts. MiR-140-3p was observed to perform its tumor suppressor function via its inhibition on cell growth, migration and invasion but its induction of cell apoptosis. Furthermore, the growth of non-small-cell lung cancer (NSCLC) cells in nude mouse models were suppressed by overexpression of miR-140-3p. ATP8A1 was demonstrated as a novel direct target of miR-140-3p using a luciferase assay. The increased level of intracellular ATP8A1 protein attenuated the inhibitor role of miR-140-3p in the growth and mobility of NSCLC cell. A regulation mechanism of miR-140-3p for the development and progression of NSCLC through downregulating the ATP8A1 expression was first discovered in the present study.

Background and Aims Nonalcoholic fatty liver disease (NAFLD) has been widely recognized as a precursor to metabolic complications. Elevated inflammation levels are predictive of NAFLD‐associated metabolic disorder. Inactive rhomboid‐like protein 2 (iRhom2) is regarded as a key regulator in inflammation. However, the precise mechanisms by which iRhom2‐regulated inflammation promotes NAFLD progression remain to be elucidated. Approach and Results Here, we report that insulin resistance, hepatic steatosis, and specific macrophage inflammatory activation are significantly alleviated in iRhom2‐deficient (knockout [KO]) mice, but aggravated in iRhom2 overexpressing mice. We further show that, mechanistically, in response to a high‐fat diet (HFD), iRhom2 KO mice and mice with iRhom2 deficiency in myeloid cells only showed less severe hepatic steatosis and insulin resistance than controls. Inversely, transplantation of bone marrow cells from healthy mice to iRhom2 KO mice expedited the severity of insulin resistance and hepatic dyslipidemia. Of note, in response to HFD, hepatic iRhom2 binds to mitogen‐activated protein kinase kinase kinase 7 (MAP3K7) to facilitate MAP3K7 phosphorylation and nuclear factor kappa B cascade activation, thereby promoting the activation of c‐Jun N‐terminal kinase/insulin receptor substrate 1 signaling, but disturbing AKT/glycogen synthase kinase 3β–associated insulin signaling. The iRhom2/MAP3K7 axis is essential for iRhom2‐regulated liver steatosis. Conclusions iRhom2 may represent a therapeutic target for the treatment of HFD‐induced hepatic steatosis and insulin resistance.