Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Organ Transplantation and Nephrosis, Shandong Institute of Nephrology, Jinan, Shandong, China.
Department of Breast and Thyroid Surgery, Tengzhou Central People's Hospital, Zaozhuang, Shandong, China.
Yonsei Med J. 2022 Jul;63(7):619-631. doi: 10.3349/ymj.2022.63.7.619.
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 cotransporter 2 (SGLT2) inhibitor canagliflozin on NAFLD in high-fat diet (HFD)-induced obese mice and possible underlying mechanisms.
Male C57BL/6 mice were fed a normal-diet, HFD, or HFD with canagliflozin for 14 weeks. AML-12 hepatocytes were treated with canagliflozin. Expression of related pathways was assessed.
Canagliflozin administration reduced body weight and fat mass, compared with HFD alone. Canagliflozin improved glucose and lipid metabolic disorders. Compared with HFD-fed mice, liver weight, serum alanine transaminase (ALT) levels, and hepatic lipid accumulation were decreased after canagliflozin administration. Additionally, canagliflozin upregulated lipolysis markers (CPT1a, ACOX1, and ACADM), downregulated lipogenesis markers (SREBP-1c and FASN), and suppressed the production of inflammatory cytokines (TNFα, MCP1, IL-1β, and IL-6), consistent with significantly increased LC3 II/I and Atg7 levels in the liver following canagliflozin treatment. In vitro, canagliflozin increased CPT1a, ACOX1, and ACADM expression, decreased SREBP-1c and FASN protein expression, and reduced TNFα, MCP1, IL-1β, and IL-6 mRNA levels in lipid mixture (LM)-induced hepatocytes in a dose-dependent manner. These changes were reversed by 3-MA, an autophagy inhibitor.
Our findings suggest that canagliflozin ameliorates the pathogenesis of NAFLD by regulating lipid metabolism and inhibiting inflammation, which may be associated with its promotion of autophagy.
非酒精性脂肪性肝病（NAFLD）与代谢性疾病密切相关，包括肥胖和糖尿病，并且已经逐渐成为最常见的慢性肝病病因。本研究旨在探讨钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂卡格列净对高脂饮食（HFD）诱导肥胖小鼠非酒精性脂肪性肝病的影响及其可能的作用机制。
雄性 C57BL/6 小鼠给予正常饮食、HFD 或 HFD 联合卡格列净喂养 14 周。AML-12 肝细胞给予卡格列净处理。检测相关通路的表达。
与单独 HFD 喂养相比，卡格列净可降低体重和脂肪量。卡格列净改善了葡萄糖和脂质代谢紊乱。与 HFD 喂养的小鼠相比，卡格列净可降低肝重、血清丙氨酸氨基转移酶（ALT）水平和肝内脂质堆积。此外，卡格列净上调了脂肪分解标志物（CPT1a、ACOX1 和 ACADM），下调了脂肪生成标志物（SREBP-1c 和 FASN），并抑制了炎症细胞因子（TNFα、MCP1、IL-1β 和 IL-6）的产生，与卡格列净处理后肝内 LC3 II/I 和 Atg7 水平明显升高一致。体外实验中，卡格列净呈剂量依赖性地增加了脂质混合物（LM）诱导的肝细胞中 CPT1a、ACOX1 和 ACADM 的表达，降低了 SREBP-1c 和 FASN 蛋白的表达，并减少了 TNFα、MCP1、IL-1β 和 IL-6 的 mRNA 水平，自噬抑制剂 3-MA 可逆转这些变化。
本研究结果表明，卡格列净通过调节脂质代谢和抑制炎症改善非酒精性脂肪性肝病的发病机制，这可能与其促进自噬有关。
