Ginsenosides Rc, as a novel SIRT6 activator, protects mice against high fat diet induced NAFLD

Zehong Yang; Yuanyuan Yu; Nannan Sun; Limian Zhou; Dong Zhang; HaiXin Chen; Wei Miao; Weihang Gao; Canyang Zhang; Changhui Liu; Xiaoying Yang; Xiaojie Wu; Yong Gao

doi:10.1016/j.jgr.2020.07.005

Ginsenosides Rc, as a novel SIRT6 activator, protects mice against high fat diet induced NAFLD

J Ginseng Res. 2023 May;47(3):376-384. doi: 10.1016/j.jgr.2020.07.005. Epub 2020 Aug 4.

Authors

Zehong Yang¹, Yuanyuan Yu¹, Nannan Sun², Limian Zhou³, Dong Zhang², HaiXin Chen¹, Wei Miao², Weihang Gao², Canyang Zhang², Changhui Liu⁴, Xiaoying Yang³, Xiaojie Wu⁵, Yong Gao^{2

6}

Affiliations

¹ Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
² Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
³ Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China.
⁴ School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
⁵ Central lab of Binzhou People's Hospital, Shandong, China.
⁶ Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, USA.

Abstract

Background: Hepatic lipid disorder impaired mitochondrial homeostasis and intracellular redox balance, triggering development of non-alcohol fatty liver disease (NAFLD), while effective therapeutic approach remains inadequate. Ginsenosides Rc has been reported to maintain glucose balance in adipose tissue, while its role in regulating lipid metabolism remain vacant. Thus, we investigated the function and mechanism of ginsenosides Rc in defending high fat diet (HFD)-induced NAFLD.

Methods: Mice primary hepatocytes (MPHs) challenged with oleic acid & palmitic acid were used to test the effects of ginsenosides Rc on intracellular lipid metabolism. RNAseq and molecular docking study were performed to explore potential targets of ginsenosides Rc in defending lipid deposition. Wild type and liver specific sirtuin 6 (SIRT6, 50721) deficient mice on HFD for 12 weeks were subjected to different dose of ginsenosides Rc to determine the function and detailed mechanism in vivo.

Results: We identified ginsenosides Rc as a novel SIRT6 activator via increasing its expression and deacetylase activity. Ginsenosides Rc defends OA&PA-induced lipid deposition in MPHs and protects mice against HFD-induced metabolic disorder in dosage dependent manner. Ginsenosides Rc (20mg/kg) injection improved glucose intolerance, insulin resistance, oxidative stress and inflammation response in HFD mice. Ginsenosides Rc treatment accelerates peroxisome proliferator activated receptor alpha (PPAR-α, 19013)-mediated fatty acid oxidation in vivo and in vitro. Hepatic specific SIRT6 deletion abolished ginsenoside Rc-derived protective effects against HFD-induced NAFLD.

Conclusion: Ginsenosides Rc protects mice against HFD-induced hepatosteatosis by improving PPAR-α-mediated fatty acid oxidation and antioxidant capacity in a SIRT6 dependent manner, and providing a promising strategy for NAFLD.

Keywords: Ginsenosides Rc; NAFLD; PPAR-α; SIRT6.