MECHANISMS OF DISORDERED HEPATIC LIPID PARTITIONING IN NON-ALCOHOLIC STEATOHEPATITIS

脂肪肝是最常见的肝病形式。它与肥胖和成熟期糖尿病密切相关。大多数脂肪肝病例不会引起并发症，但当炎症和肝损伤也发生时，在非酒精性脂肪性肝炎或NASH的情况下，可能导致肝瘢痕形成并最终导致肝硬化或肝癌。为什么一些患有脂肪肝的人会发展成NASH而另一些人不会（良性或单纯性脂肪变性）的原因尚不清楚，这是本研究的主题。这些研究将在一种新的肥胖和糖尿病小鼠模型中进行，这种肥胖的澳大利亚小鼠，所有的动物在几个月后都会患上脂肪肝。当肥胖的澳大利亚小鼠被喂食麦克唐纳饮食[高饱和脂肪]时，它们会发展成全面的NASH并伴有肝脏瘢痕。在澳大利亚肥胖小鼠出现NASH之前，脂联素（一种由脂肪储存细胞产生的蛋白质）的血液水平下降。与高血胰岛素和高血糖水平一起，提出这些变化是导致肝脏中脂肪（脂质）分子异常高的原因，以至于脂肪最终在称为脂毒性的过程中损害肝脏。计划中的研究将首先测试这一假设是否正确，然后着手研究预防或逆转肝脏中这种危险的脂肪堆积的方法。策略包括高橄榄油饮食（在另一种脂肪性肝炎模型中具有保护作用），纠正血液脂联素水平，降低胰岛素和血糖水平。预期的结果是更好地了解脂肪肝疾病的并发症是如何发生的，因此可以深入了解如何在易感人群中预防或逆转这种疾病。

Fatty liver is the commonest form of liver disease. It is strongly associated with obesity and maturity onset diabetes. The majority of cases of fatty liver disease cause no complications, but when inflammation and liver damage also occur, in the condition of non-alcoholic steatohepatitis or NASH, liver scarring and eventually cirrhosis or liver cancer can result. The reason why some people with fatty liver disease develop NASH and others do not (benign or simple steatosis) is unknown and is the subject of this research. The studies will be performed in a novel mouse model of obesity and diabetes, the fat aussie mouse, in which all animals develop fatty liver disease after a few months. When fat aussie mice are fed a Macdonald's diet [high in saturated fat] they develop full-blown NASH with liver scarring. Before NASH develops in fat aussie mice, blood levels of adiponectin (a protein produced from fat storage cells) fall. Together with high blood insulin and high blood sugar levels, it is proposed that these changes are what leads to an extraordinarily high build up of fat (lipid) molecules in the liver, to the extent that the fat ultimately damages the liver in a process called lipotoxicity. The planned research will first test whether this hypothesis is correct, and then set about ways to prevent or reverse such a dangerous build up of fats in the liver. Strategies include a high olive oil diet (which is protective in another model of steatohepatitis), correction of blood adiponectin levels, lowering of insulin and blood sugar levels. The anticipated results are a much better understanding of how complications come about in fatty liver disease, and therefore insights into how this disorder can be prevented or reversed in those who are predisposed.