Bicyclol alleviates obesity-induced renal injury by inhibiting JNK and NF-κB-mediated inflammation.

Obesity is recognized as a major risk factor for chronic kidney disease (CKD), which is accompanied by increased renal lipid build-up, fibrosis, inflammation, apoptosis and pyroptosis. Bicyclol (BIC), a Chinese marketed hepatoprotective drug, has shown excellent anti-inflammatory, anti-fibrosis, anti-apoptotic, and lipid regulation effects in different animal models. In this study, we explored the role and mechanism of BIC in high-fat diet (HFD)-induced obesity-related nephropathy. Mice were fed with HFD for 24 weeks to develop obesity-related nephropathy, while mice in the BIC administration group were treated with BIC (50 mg/kg or 100 mg/kg, once every two days) at the last 12 weeks. We found that BIC treatment relieved the impairment of kidney structure and renal dysfunction caused by HFD. In addition, we found that BIC mitigated HFD-induced renal fibrosis, inflammation, apoptosis and pyroptosis by inhibiting JNK and NF-κB pathways. SV40-MES-13 cells treated with palmitate (PA) were used as the in vitro model. Our data show that BIC pre-administration relieved cellular damage caused by PA through suppressing JNK and NF-κB signaling pathways. In conclusion, we demonstrated that BIC attenuated obesity-induced renal injury by inhibiting chronic inflammation, fibrosis, apoptosis and pyroptosis via targeting JNK and NF-κB pathways. Our data suggested that BIC could be potentially used to prevent obesity-associated nephropathy, which warrants future investigation.

Macrophage-specific FGFR1 deletion alleviates high-fat-diet-induced liver inflammation by inhibiting the MAPKs/TNF pathways.

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disease that is substantially associated with obesity-induced chronic inflammation. Macrophage activation and macrophage-medicated inflammation play crucial roles in the development and progression of NAFLD. Furthermore, fibroblast growth factor receptor 1 (FGFR1) has been shown to be essentially involved in macrophage activation. This study investigated the role of FGFR1 in the NAFLD pathogenesis and indicated that a high-fat diet (HFD) increased p-FGFR1 levels in the mouse liver, which is associated with increased macrophage infiltration. In addition, macrophage-specific FGFR1 knockout or administration of FGFR1 inhibitor markedly protected the liver from HFD-induced lipid accumulation, fibrosis, and inflammatory responses. The mechanistic study showed that macrophage-specific FGFR1 knockout alleviated HFD-induced liver inflammation by suppressing the activation of MAPKs and TNF signaling pathways and reduced fat deposition in hepatocytes, thereby inhibiting the activation of hepatic stellate cells. In conclusion, the results of this research revealed that FGFR1 could protect the liver of HFD-fed mice by inhibiting MAPKs/TNF-mediated inflammatory responses in macrophages. Therefore, FGFR1 can be employed as a target to prevent the development and progression of NAFLD.