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KMID : 0311120220630070619
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Yonsei Medical Journal
2022 Volume.63 No. 7 p.619 ~ p.631
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Canagliflozin Ameliorates Nonalcoholic Fatty Liver Disease by Regulating Lipid Metabolism and Inhibiting Inflammation through Induction of Autophagy
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Xu Zhipeng
Hu Wenxin
Wang Bin
Xu Ting
Wang Jianning
Wei Dan
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Abstract
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Purpose: Nonalcoholic fatty liver disease (NAFLD) is closely associated with metabolic diseases, including obesity and diabetes,and has gradually become the most common cause of chronic liver disease. We investigated the effects of sodium glucose cotrans porter 2 (SGLT2) inhibitor canagliflozin on NAFLD in high-fat diet (HFD)-induced obese mice and possible underlying mecha nisms.
Materials and Methods: Male C57BL/6 mice were fed a normal-diet, HFD, or HFD with canagliflozin for 14 weeks. AML-12 hepa tocytes were treated with canagliflozin. Expression of related pathways was assessed.
Results: Canagliflozin administration reduced body weight and fat mass, compared with HFD alone. Canagliflozin improved glu cose and lipid metabolic disorders. Compared with HFD-fed mice, liver weight, serum alanine transaminase (ALT) levels, and he patic lipid accumulation were decreased after canagliflozin administration. Additionally, canagliflozin upregulated lipolysis mark ers (CPT1a, ACOX1, and ACADM), downregulated lipogenesis markers (SREBP-1c and FASN), and suppressed the production ofinflammatory cytokines (TNFα, MCP1, IL-1β, and IL-6), consistent with significantly increased LC3 II/I and Atg7 levels in the liverfollowing canagliflozin treatment. In vitro, canagliflozin increased CPT1a, ACOX1, and ACADM expression, decreased SREBP-1cand FASN protein expression, and reduced TNFα, MCP1, IL-1β, and IL-6 mRNA levels in lipid mixture (LM)-induced hepatocytesin a dose-dependent manner. These changes were reversed by 3-MA, an autophagy inhibitor.
Conclusion: Our findings suggest that canagliflozin ameliorates the pathogenesis of NAFLD by regulating lipid metabolism andinhibiting inflammation, which may be associated with its promotion of autophagy.
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KEYWORD
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Canagliflozin, nonalcoholic fatty liver disease, high-fat diet, lipid metabolism, inflammation, autophagy
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