MECHANISMS OF DISORDERED HEPATIC LIPID PARTITIONING IN NON-ALCOHOLIC STEATOHEPATITIS

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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.