Tang Youcai, Zheng Shizhong, Chen Anping
Department of Pathology, School of Medicine, Saint Louis University, 1100 S. Grand Boulevard, St. Louis, Missouri 63104, USA.
Endocrinology. 2009 Jul;150(7):3011-20. doi: 10.1210/en.2008-1601. Epub 2009 Mar 19.
Nonalcoholic steatohepatitis (NASH) is commonly found in patients with obesity and is often accompanied with abnormally elevated levels of plasma leptin, i.e. hyperleptinemia. A relatively high population of NASH patients develops hepatic fibrosis, even cirrhosis. Hepatic stellate cells (HSCs) are the major effector cells during liver fibrogenesis and could be activated by leptin. The antioxidant curcumin, a phytochemical from turmeric, has been shown to suppress HSC activation in vitro and in vivo. This project is to evaluate the effect of curcumin on leptin-induced HSC activation and to elucidate the underlying mechanisms. We hypothesize that curcumin abrogates the stimulatory effect of leptin on HSC activation by interrupting leptin signaling and attenuating leptin-induced oxidative stress. Curcumin eliminates the stimulatory effects of leptin on regulating expression of genes closely relevant to HSC activation. Curcumin interrupts leptin signaling by reducing phosphorylation levels of leptin receptor (Ob-R) and its downstream intermediators. In addition, curcumin suppresses gene expression of Ob-R in HSCs, which requires the activation of endogenous peroxisome proliferator-activated receptor-gamma and de novo synthesis of glutathione. In conclusion, our results demonstrate that curcumin abrogates the stimulatory effect of leptin on HSC activation in vitro by reducing the phosphorylation level of Ob-R, stimulating peroxisome proliferator-activated receptor-gamma activity, and attenuating oxidative stress, leading to the suppression of Ob-R gene expression and interruption of leptin signaling. These results provide novel insights into therapeutic mechanisms of curcumin in inhibiting HSC activation and intervening liver fibrogenesis associated with hyperleptinemia in NASH patients.
非酒精性脂肪性肝炎（NASH）常见于肥胖患者，且常伴有血浆瘦素水平异常升高，即高瘦素血症。相当一部分NASH患者会发展为肝纤维化，甚至肝硬化。肝星状细胞（HSCs）是肝脏纤维化形成过程中的主要效应细胞，可被瘦素激活。抗氧化剂姜黄素是一种从姜黄中提取的植物化学物质，已被证明在体外和体内均可抑制肝星状细胞的激活。本项目旨在评估姜黄素对瘦素诱导的肝星状细胞激活的影响，并阐明其潜在机制。我们假设姜黄素通过中断瘦素信号传导和减轻瘦素诱导的氧化应激来消除瘦素对肝星状细胞激活的刺激作用。姜黄素消除了瘦素对调节与肝星状细胞激活密切相关基因表达的刺激作用。姜黄素通过降低瘦素受体（Ob-R）及其下游介质的磷酸化水平来中断瘦素信号传导。此外，姜黄素抑制肝星状细胞中Ob-R的基因表达，这需要内源性过氧化物酶体增殖物激活受体-γ的激活和谷胱甘肽的从头合成。总之，我们的结果表明，姜黄素通过降低Ob-R的磷酸化水平、刺激过氧化物酶体增殖物激活受体-γ活性和减轻氧化应激，在体外消除了瘦素对肝星状细胞激活的刺激作用，从而导致Ob-R基因表达的抑制和瘦素信号传导的中断。这些结果为姜黄素抑制肝星状细胞激活和干预NASH患者中与高瘦素血症相关的肝纤维化形成的治疗机制提供了新的见解。
