Phosphatidylcholine protects against steatosis in mice but not non-alcoholic steatohepatitis.

摘要

Several studies suggest that low levels of hepatic phosphatidylcholine (PC) play a role in the pathogenesis of non-alcoholic steatohepatitis (NASH). CTP: phosphocholine cytidylyltransferase (CT) is the key regulatory enzyme in the CDP-choline pathway for PC biosynthesis. Liver-specific elimination of CTalpha (LCTalpha(-/-)) in mice fed a chow diet decreases very-low-density lipoprotein secretion, reduces lipid efflux from liver, and causes mild steatosis. We fed LCTalpha(-/-) mice a high fat diet to determine if impaired PC biosynthesis played a role in development of NASH. LCTalpha(-/-) mice developed NASH within one week of high fat feeding. Hepatic CTalpha deficiency caused hepatic steatosis, a 2-fold increase in ceramide mass, and a 20% reduction in PC content. In an attempt to prevent NASH, LCTalpha(-/-) mice were either injected daily with CDP-choline or fed the high fat diet supplemented with betaine. In addition, LCTalpha(-/-) mice were injected with adenoviruses expressing CTalpha. CDP-choline injections and adenoviral expression of CTalpha increased hepatic PC, while dietary betaine supplementation normalized hepatic triacylglycerol but did not alter hepatic PC mass in LCTalpha(-/-) mice. Interestingly, none of the treatments normalized hepatic ceramide mass or fully prevented the development of NASH in LCTalpha(-/-) mice. These results show that normalizing the amount of hepatic PC is not sufficient to prevent NASH in LCTalpha(-/-) mice.