Hepatic RACK1 deletion disturbs lipid and glucose homeostasis independently of insulin resistance.

By: Qin, Wanying; Zhang, Ting; Ge, Mingxia; Zhou, Huimin; Xu, Yuhui; Mu, Rongfang; Huang, Chaoguang; Liu, Daowei; Huang, Bangrui; Wang, Qian; Kong, Qinghua; Kong, Qingpeng; Li, Fei; Xiong, Wenyong

The Journal of endocrinology

DOI：https://doi.org/10.1530/JOE-22-0076

Published：2022-May-01

Abstract

Receptor for Activated C Kinase 1 (RACK1) is a versatile protein involves in multiple biological processes. In a previous study by Zhao et al., hepatic RACK1 deletion in mice led to an inhibition of autophagy, blocked autophagy-dependent lipolysis and caused steatosis. Using the same mouse model (RACK1hep-/-), we revealed new roles of RACK1 in maintaining bile acid homeostasis and hepatic glucose uptake, which further affected circulatory lipid and glucose level. To be specific, even under hepatic steatosis, the plasma lipids were generally reduced in RACK1hep-/- mouse, which was due to the suppression of intestinal lipid absorption. Accordingly, a decrease of total bile acid level was found in RACK1hep-/- livers, gallbladders and small intestine tissues, and specific decrease of 12-hydroxylated bile acids was detected by LC-MS. Consistently, reduced expression of CYP8B1 was found. A decrease of hepatic glycogen storage was also observed, which might be due to the inhibited glucose uptake by GLUT2 insufficiency. Interestingly, RACK1-KO-inducing hepatic steatosis did not raise insulin resistance (IR), nor IR-inducing factors like ER stress and inflammation. In summary, this study uncovers that hepatic RACK1 might be required in maintaining bile acid homeostasis and glucose uptake in hepatocytes. This study also provides an additional case of hepatic steatosis disassociation with insulin resistance.