Molecular pathological analysis of pathogenesis of non-alcoholic steatohepatitis: Propose of new treatment approach

代谢综合征是世界范围内最重要的疾病之一。糖尿病、动脉硬化和脑血管疾病等严重的不治之症是由内脏脂肪中的脂肪过度沉积引起的。近年来，代谢综合征的肝脏表现为非酒精性脂肪性肝病(NAFLD)。尤其是非酒精性脂肪性肝炎(NASH)，这是NAFLD的严重表型，由于其在西方人中的患病率越来越高，因此引起了人们的严重关注。重要的是，即使在年轻一代，NASH最终也可能导致肝硬变和肝细胞癌的发展。为了阐明肥胖条件下NAFLD的发病机制，我们根据不同的疾病情况建立了几种独特的动物模型。高胆固醇喂养的大鼠和兔表现出典型的细长纤维化和肝脏脂质过载，类似于人的肝纤维化。Galectin-3基因敲除小鼠、谷氨酸单钠处理小鼠和SHR/NDmcr-cp大鼠表现出中心性肥胖、2型糖尿病和明显的脂肪改变，并伴有明显的炎症反应，以雄性为主。我们分析了这些表现出NASH样肝脏病理的动物以及患有NASH的人类肝脏标本。在本研究中，我们成功地阐明了脂质过氧化、氧化应激和糖基化在NASH疾病进展中的重要作用。此外，我们还用几种传统草药阐明了NASH的预防作用。寻找包括NASH在内的治疗代谢综合征的有效药物，是代谢综合征候选人群初级保健最重要的贡献之一。我们将继续利用我们的动物模型寻找一些有效的天然产品。

Metabolic syndrome is one of the most important disease conditions in all over the world. Severe and incurable diseases such as diabetes mellitus, arteriosclerosis and cerebro-vascular diseases were induced from lipid overdeposition in visceral fat. Recently, hepatic manifestation of metabolic syndrome was noted as non-alcoholic fatty liver diseases (NAFLD). Especially, non alcoholic steatohepatitis (NASH), which is severe phenotype of NAFLD is of a serious concern due to its increasing prevalence in the westernized world. Importantly, NASH may ultimately lead to the development of liver cirrhosis and hepatocellular carcinoma even in young generation. To make clarify the disease mechanism of NAFLD under the condition of obesity, we developed several unique animal models based on different disease condition. High-cholesterol fed rat and rabbit showed typical slender fibrosis as well as lipid overload in the liver, similar to human liver fibrosis. While Galectin-3 knock out mice, monosodium-glutamate treated mice and SHR/NDmcr-cp rats showed central obese, type 2 diabetes and marked fatty change with inflammation in predominant to male. We analyzed these animals showing NASH-like liver pathology as well as human liver specimens suffering NASH. In present study, we succeeded to clarify that lipid peroxidation, oxidative stress and glycation play important roles for disease progress of NASH. In addition, we made clarify the preventional roles of NASH using several traditional herval medicines. To find the effective products for metabolic syndrome including NASH is one of the most important contribution for primary care of peoples candidate of metabolic syndrome. We will continue to seek some effective natural products using our animal models.