Deletion of Macrophage Mineralocorticoid Receptor Protects Hepatic Steatosis and Insulin Resistance Through ER{alpha}/HGF/Met Pathway

We report that myeloid MR knockout (MRKO) improves glucose intolerance, insulin resistance, and hepatic steatosis in obese mice. Estrogen signaling is sufficient and necessary for such improvements. Hepatic gene and protein expression suggests that MRKO reduces hepatic lipogenesis and lipid storage. In the presence of estrogen, MRKO in macrophages decreases lipid accumulation and increases insulin sensitivity of hepatocytes through hepatocyte growth factor (HGF)/Met signaling. MR directly regulates estrogen receptor 1 (Esr1 [encoding ERα]) in macrophages. Knockdown of hepatic Met eliminates the beneficial effects of MRKO in female obese mice. These findings identify a novel MR/ERα/HGF/Met pathway that conveys metabolic signaling from macrophages to hepatocytes in hepatic steatosis and insulin resistance and provide potential new therapeutic strategies for NAFLD and T2DM.

Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Zhang, Y.-Y.; Li, C.; Yao, G.-F.; Du, L.-J.; Liu, Y.; Zheng, X.-J.; Yan, S.; Sun, J.-Y.; Liu, Y.; Liu, M.-Z.; Zhang, X.; Wei, G.; Tong, W.; Chen, X.; Wu, Y.; Sun, S.; Liu, S.; Ding, Q.; Yu, Y.; Yin, H.; Duan, S.-Z. Tags: Metabolism Source Type: research