Canagliflozin Ameliorates Nonalcoholic Fatty Liver Disease by Regulating Lipid Metabolism and Inhibiting Inflammation through Induction of Autophagy.
Canagliflozin Ameliorates Nonalcoholic Fatty Liver Disease by Regulating Lipid Metabolism and Inhibiting Inflammation through Induction of Autophagy.
复制标题
Canagliflozin通过诱导自噬调节脂质代谢和抑制炎症来改善非酒精性脂肪肝。
DOI：
10.3349/ymj.2022.63.7.619
复制
发表时间：
2022-07
影响因子：
2.4
通讯作者：
Wei, Dan
中科院分区：
文献类型：
--
作者：
Xu, Zhipeng;Hu, Wenxin;Wang, Bin;Xu, Ting;Wang, Jianning;Wei, Dan
关键词：
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，并已逐渐成为慢性肝病的最常见原因。我们研究了钠葡萄糖协同转运蛋白2（SGLT 2）抑制剂卡格列净对高脂饮食（HFD）诱导的肥胖小鼠NAFLD的影响及其可能的潜在机制。雄性C57 BL/6小鼠喂食正常饮食、HFD或含卡格列净的HFD 14周。用卡格列净处理AML-12肝细胞。评估相关通路的表达。与HFD单独给药相比，卡格列净给药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。与喂食HFD的小鼠相比，卡格列净给药后肝脏重量、血清丙氨酸转氨酶（ALT）水平和肝脏脂质蓄积降低。此外，卡格列净上调脂解标志物（CPT 1a、ACOX 1和ACADM），下调脂肪生成标志物（SREBP-1c和Fn），并抑制炎性细胞因子（TNFα、MCP 1、IL-1β和IL-6）的产生，这与卡格列净治疗后肝脏中LC 3 II/I和Atg 7水平显著升高一致。在体外，卡格列净以剂量依赖性方式增加脂质混合物（LM）诱导的肝细胞中CPT 1a、ACOX 1和ACADM表达，降低SREBP-1c和Fn蛋白表达，并降低TNFα、MCP 1、IL-1β和IL-6 mRNA水平。这些变化被自噬抑制剂3-MA逆转。我们的研究结果表明，卡格列净通过调节脂质代谢和抑制炎症来改善NAFLD的发病机制，这可能与其促进自噬有关。
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.
登录
查看更多内容
影响因子：
29.4
作者：
Goldberg D;Ditah IC;Saeian K;Lalehzari M;Aronsohn A;Gorospe EC;Charlton M
通讯作者：
Charlton M
影响因子：
64.8
作者：
Liu, Zixu;Mar, Katrina B.;Alto, Neal M.
通讯作者：
Alto, Neal M.
影响因子：
5
作者：
Kabil, Soad L.;Mahmoud, Nevertyty M.
通讯作者：
Mahmoud, Nevertyty M.
影响因子：
8.1
作者：
Pafili K;Roden M
通讯作者：
Roden M
通过自噬调节肝脏代谢。
影响因子：
29.4
作者：
Madrigal-Matute J;Cuervo AM
通讯作者：
Cuervo AM