PDF(Pubmed)
Abstract：
Type 2 diabetes mellitus (T2DM) increases the risk of non-alcoholic fatty liver disease (NAFLD) progression to advanced stages, especially upon high-fat diet (HFD). HFD-induced hepatic fibrosis can be marked by oxidative stress, inflammation, and activation of hepatic stellate cells. Sirtuin 1/2 (SIRT1/2), NAD-dependent class III histone deacetylases, are involved in attenuation of fibrosis. In our conducted research, TGF-β1-activated LX-2 cells, free fatty acid (FFA)-treated simultaneous co-culture (SCC) cells, and HFD-induced hepatic fibrosis in Zucker diabetic fatty (ZDF) rats, a widely used animal model in the study of metabolic syndromes, were used to evaluate the protective effect of Tenovin-1, a SIRT1/2 inhibitor. ZDF rats were divided into chow diet, HFD, and HFD + Tenovin-1 groups. Tenovin-1 reduced hepatic damage, inhibited inflammatory cell infiltration, micro/ macro-vesicular steatosis and prevented collagen deposition HFD-fed rats. Tenovin-1 reduced serum biochemical parameters, triglyceride (TG) and malondialdehyde (MDA) levels but increased glutathione, catalase, and superoxide dismutase levels. Tenovin-1 mitigated proinflammatory cytokines IL-6, IL-1β, TNFα and fibrosis biomarkers in HFD rats, TGF-β1-activated LX-2 and FFA treated SCC cells. Additionally, Tenovin-1 suppressed SIRT1/2 expression and inhibited JNK-1 and STAT3 phosphorylation in HFD rats and FFA-treated SCC cells. In conclusion, Tenovin-1 attenuates hepatic fibrosis by stimulating antioxidants and inhibiting inflammatory cytokines under HFD conditions in diabetic rats.
摘要：
2型糖尿病（T2DM）增加非酒精性脂肪性肝病（NAFLD）进展至晚期的风险，特别是在高脂肪饮食（HFD）。HFD诱导的肝纤维化可以通过氧化应激来标记，炎症,和激活肝星状细胞。Sirtuin1/2(SIRT1/2),NAD依赖性III类组蛋白脱乙酰酶，参与纤维化的减弱。在我们进行的研究中，TGF-β1激活的LX-2细胞,游离脂肪酸（FFA）处理的同时共培养（SCC）细胞，和HFD诱导的Zucker糖尿病脂肪（ZDF）大鼠肝纤维化，在代谢综合征研究中广泛使用的动物模型，用于评估SIRT1/2抑制剂Tenovin-1的保护作用。ZDF大鼠分为饮食，HFD,和HFD+Tenovin-1组。Tenovin-1减少肝损伤，抑制炎症细胞浸润，微/大泡脂肪变性和预防胶原沉积HFD喂养的大鼠。Tenovin-1降低血清生化指标，甘油三酯（TG）和丙二醛（MDA）水平，但增加谷胱甘肽，过氧化氢酶,和超氧化物歧化酶水平。Tenovin-1减轻促炎细胞因子IL-6，IL-1β，HFD大鼠的TNFα和纤维化生物标志物，TGF-β1激活的LX-2和FFA处理的SCC细胞。此外,Tenovin-1在HFD大鼠和FFA处理的SCC细胞中抑制SIRT1/2表达并抑制JNK-1和STAT3磷酸化。总之,Tenovin-1通过刺激抗氧化剂和抑制HFD条件下糖尿病大鼠的炎症细胞因子来减轻肝纤维化。
