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 3ß-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.

Oral flavonoid fisetin treatment protects against prolonged high-fat-diet-induced cardiac dysfunction by regulation of multicombined signaling.

Excess high-fat diet (HFD) intake predisposes the occurrence of obesity-associated heart injury, but the mechanism is elusive. Fisetin (FIS), as a natural flavonoid, has potential activities to alleviate obesity-induced metabolic syndrome. However, the underlying molecular mechanisms of FIS against HFD-induced cardiac injury remain unclear. The present study was to explore the protective effects of FIS on cardiac dysfunction in HFD-fed mice. We found that FIS alleviated HFD-triggered metabolic disorder by reducing body weight, fasting blood glucose and insulin levels, and insulin resistance. Moreover, FIS supplements significantly alleviated dyslipidemia in both mouse hearts and cardiomyocytes stimulated by metabolic stress. FIS treatment abolished HFD-induced inflammatory response in heart tissues through suppressing TNF receptor-1/TNF receptor-associated factor-2 (Tnfr-1/Traf-2) signaling. Furthermore, FIS induced a strong reduction in the expression of fibrosis-related genes, contributing to the inhibition of fibrosis by inactivating transforming growth factor (Tgf)-ß1/Smads/Erk1/2 signaling. Collectively, these results demonstrated that FIS could be a promising therapeutic strategy for the treatment of obesity-associated cardiac injury.