薯蓣皂苷元通过调节 SIRT6 相关的脂肪酸摄取来减轻 2 型糖尿病非酒精性脂肪肝疾病。
Diosgenin attenuates non-alcoholic fatty liver disease in type 2 diabetes through regulating SIRT6-related fatty acid uptake.
机构信息
Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
出版信息
Phytomedicine. 2023 Mar;111:154661. doi: 10.1016/j.phymed.2023.154661. Epub 2023 Jan 10.
BACKGROUND
More than 70% of patients with type 2 diabetes (T2DM) concomitantly suffer from Non-alcoholic fatty liver disease (NAFLD), and the coexistence and interaction of them increases the intractability of NAFLD. With the protective effect against hepatic steatosis and liver fibrosis, SIRT6 is becoming a notable target of NAFLD. Diosgenin, an active monomer from Chinese herbs, has been reported to protect against NAFLD.
PURPOSE
This study aims to figure out the mechanism how diosgenin alleviate NAFLD in T2DM and the relationship with SIRT6.
METHODS
In vivo studies used spontaneous diabetic db/db mice and divided them into two parts. The first part included four groups consisting of control (Con) group, model (Mod) group, low dose of diosgenin (DL) group and high dose of diosgenin (DH) group. The second part included four groups consisting of Con group, Mod group, DH+OSS (OSS_128167, inhibitor of SIRT6) group, MDL (MDL800, agonist of SIRT6) group. HepG2 cell line was selected in study in vitro, which was mainly composed of six groups including Con group, palmitic acid (PA) group, PA+DL group, PA+DH group, PA+DH+OSS group, PA+MDL group. OGTT, Biochemical biomarker (including TG, TC, AST, ALT), inflammatory biomarker (including IL-6 and TNF-α) were measured. HE, Oil Red O, and DHE staining were conducted. Immunohistochemistry, immunofluorescence, mRNA-seq, and qPCR were used to explore the mechanism.
RESULTS
Results in the first part of study in vivo indicated that diosgenin protected against lipid accumulation, oxidative stress, cell injury, and light inflammatory of liver in db/db mice and regulated the expression of SIRT6 and fatty acid transporter including CD36, FATP2, FABP1. The effect of diosgenin could be reversed in DH+OSS group and the same effect was observed in MDL group in the second part of study in vivo. The same results were also noted in followed study in vitro. Diosgenin inhibited the fatty acids uptake and regulated the expression of SIRT6 and fatty acid transporter including CD36, FATP2, and FABP1 in PA-induced hepG2 cells, and which was reversed in DH+OSS group and resembled in MDL group.
CONCLUSIONS
Diosgenin could attenuate non-alcoholic fatty liver disease in type 2 diabetes through regulating SIRT6-related fatty acid uptake.
背景
超过 70%的 2 型糖尿病（T2DM）患者同时患有非酒精性脂肪性肝病（NAFLD），两者共存和相互作用增加了 NAFLD 的难治性。SIRT6 对肝脂肪变性和肝纤维化具有保护作用，因此成为 NAFLD 的一个显著靶点。薯蓣皂苷元是一种来自中草药的活性单体，已有研究报道其具有防治 NAFLD 的作用。
目的
本研究旨在探讨薯蓣皂苷元缓解 T2DM 合并 NAFLD 的作用机制及其与 SIRT6 的关系。
方法
体内研究采用自发性糖尿病 db/db 小鼠，将其分为两部分。第一部分包括 4 组：对照组（Con）、模型组（Mod）、低剂量薯蓣皂苷元（DL）组和高剂量薯蓣皂苷元（DH）组。第二部分包括 4 组：Con 组、Mod 组、DH+OSS（OSS_128167，SIRT6 抑制剂）组、MDL（MDL800，SIRT6 激动剂）组。体外研究采用 HepG2 细胞系，主要包括 6 组：对照组（Con）、棕榈酸（PA）组、PA+DL 组、PA+DH 组、PA+DH+OSS 组、PA+MDL 组。检测 OGTT、生化标志物（包括 TG、TC、AST、ALT）、炎症标志物（包括 IL-6 和 TNF-α）。进行 HE、油红 O 和 DHE 染色。采用免疫组化、免疫荧光、mRNA 测序和 qPCR 等方法探讨其作用机制。
结果
体内研究第一部分结果表明，薯蓣皂苷元可改善 db/db 小鼠的脂质蓄积、氧化应激、细胞损伤和肝脏轻度炎症，并调节 SIRT6 和脂肪酸转运体（包括 CD36、FATP2、FABP1）的表达。DH+OSS 组可逆转薯蓣皂苷元的作用，体内研究第二部分的 MDL 组也观察到相同的结果。体外后续研究也得到了类似的结果。薯蓣皂苷元可抑制脂肪酸摄取，并调节 SIRT6 和脂肪酸转运体（包括 CD36、FATP2 和 FABP1）的表达，这种作用在 PA 诱导的 HepG2 细胞中被 DH+OSS 组逆转，与 MDL 组相似。
结论
薯蓣皂苷元可能通过调节 SIRT6 相关的脂肪酸摄取来减轻 2 型糖尿病合并的非酒精性脂肪性肝病。
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