iRhom2 Promotes Hepatic Steatosis by Activating MAP3K7‐Dependent Pathway

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.