Drug Design, Development and Therapy (May 2021)
Canagliflozin Facilitates Reverse Cholesterol Transport Through Activation of AMPK/ABC Transporter Pathway
Abstract
Yingnan Zhao,1,2 Yanping Li,2 Qinhui Liu,1 Qin Tang,1,2 Zijing Zhang,1,2 Jinhang Zhang,1,2 Cuiyuan Huang,1,2 Hui Huang,1,2 Guorong Zhang,1,2 Jian Zhou,1,2 Jiamin Yan,1,2 Yan Xia,1,2 Zhiyong Zhang,1,2 Jinhan He1,2 1Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 2Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of ChinaCorrespondence: Zhiyong Zhang; Jinhan HeDepartment of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of ChinaTel/Fax +86-28-85426416Email [email protected]; [email protected] and Purpose: Cholesterol is an essential lipid and its homeostasis is a major factor for many diseases, such as hyperlipidemia, atherosclerosis, diabetes, and obesity. Sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Cana) is a new kind of hypoglycemic agent, which decreases urinary glucose reabsorption and reduces hyperglycemia. Cana has been shown to regulate serum lipid, decrease serum triglyceride and increase serum high-density lipoprotein-cholesterol (HDL-C), and improve cardiovascular outcomes. But evidence of how Cana impacted the cholesterol metabolism remains elusive.Methods: We treated Cana on mice with chow diet or western diet and then detected cholesterol metabolism in the liver and intestine. To explore the mechanism, we also treated hepG2 cells and Caco2 cells with different concentrations of Cana.Results: In this study, we showed that Cana facilitated hepatic and intestinal cholesterol efflux. Mechanically, Cana via activating adenosine monophosphate-activated protein kinase (AMPK) increased the expression of ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 in liver and intestine, increased biliary and fecal cholesterol excretion.Conclusion: This research confirms that Cana regulates cholesterol efflux and improves blood and hepatic lipid; this may be a partial reason for improving cardiovascular disease.Keywords: canagliflozin, ATP-binding cassette (ABC) transporters G5/8, cholesterol efflux, AMPK
