MECHANISMS OF DISORDERED HEPATIC LIPID PARTITIONING IN NON-ALCOHOLIC STEATOHEPATITIS

非酒精性脂肪性肝炎中肝脏脂质分配紊乱的机制

• 批准号: nhmrc : 418101
• 负责人: Prof Christopher Nolan
• 金额: $ 29.98万
• 依托单位: Australian National University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/mechanisms-disordered-hepatic-alcoholic-steatohepatitis/81613
• 关键词: MECHANISMS; DISORDERED; HEPATIC; LIPID; PARTITIONING

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.

脂肪肝是最常见的肝脏疾病。它与肥胖和成熟型糖尿病密切相关。大多数脂肪肝病例不会引起并发症，但当炎症和肝损害同时发生时，在非酒精性脂肪性肝炎或NASH的情况下，肝瘢痕形成并最终导致肝硬化或肝癌。为什么一些脂肪肝患者会发展为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，这也是本研究的主题。这些研究将在一种新型的肥胖和糖尿病小鼠模型中进行，即肥胖的澳大利亚小鼠，在这种小鼠中，所有动物在几个月后都会患上脂肪肝疾病。当肥胖的澳洲老鼠被喂食麦当劳饮食（高饱和脂肪）时，它们会发展成完全的NASH，并伴有肝脏疤痕。在肥胖的澳大利亚小鼠发生NASH之前，血液中的脂联素（一种由脂肪储存细胞产生的蛋白质）水平下降。再加上高胰岛素和高血糖水平，这些变化导致了肝脏中脂肪（脂质）分子的高度积聚，达到了脂肪最终损害肝脏的程度，这一过程被称为脂肪毒性。计划中的研究将首先检验这一假设是否正确，然后着手采取措施防止或逆转肝脏中这种危险的脂肪堆积。策略包括高橄榄油饮食（这对另一种脂肪性肝炎有保护作用），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理解脂肪性肝病的并发症是如何产生的，从而深入了解如何预防或逆转那些易患脂肪性肝病的人。