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
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China.
University of the Chinese Academy of Sciences, Beijing, People's Republic of China.
J Endocrinol. 2022 Aug 12;254(3):137-151. doi: 10.1530/JOE-22-0076. Print 2022 Sep 1.
Receptor for activated C kinase 1 (RACK1) is a versatile protein involved 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 levels. 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 in 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 liquid chromatography-mass spectrometry. Consistently, reduced expression of CYP8B1 was found. A decrease in 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 endoplasmic reticulum 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.
活化C激酶1受体（RACK1）是一种参与多种生物学过程的多功能蛋白质。在Zhao等人先前的一项研究中，小鼠肝脏中RACK1的缺失导致自噬受到抑制，阻断了自噬依赖性脂解作用，并引起脂肪变性。使用相同的小鼠模型（RACK1hep-/-），我们揭示了RACK1在维持胆汁酸稳态和肝脏葡萄糖摄取方面的新作用，这进一步影响了循环脂质和葡萄糖水平。具体而言，即使在肝脏脂肪变性的情况下，RACK1hep-/-小鼠的血浆脂质总体上也会降低，这是由于肠道脂质吸收受到抑制。因此，在RACK1hep-/-肝脏、胆囊和小肠组织中发现总胆汁酸水平降低，并且通过液相色谱-质谱法检测到12-羟基化胆汁酸有特异性降低。一致地，发现CYP8B1的表达减少。还观察到肝脏糖原储存减少，这可能是由于GLUT2功能不足导致葡萄糖摄取受到抑制。有趣的是，RACK1基因敲除诱导的肝脏脂肪变性并未增加胰岛素抵抗（IR），也未增加诸如内质网应激和炎症等IR诱导因子。总之，本研究揭示肝脏RACK1可能是维持肝细胞胆汁酸稳态和葡萄糖摄取所必需的。本研究还提供了肝脏脂肪变性与胰岛素抵抗分离的另一个案例。
