title: Phosphatidylcholine protects against steatosis in mice but not non-alcoholic steatohepatitis.
abstract: 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 CTα (LCTα(-/-)) in mice fed a chow diet decreases very-low-density lipoprotein secretion, reduces lipid efflux from liver, and causes mild steatosis. We fed LCTα(-/-) mice a high fat diet to determine if impaired PC biosynthesis played a role in development of NASH. LCTα(-/-) mice developed NASH within one week of high fat feeding. Hepatic CTα deficiency caused hepatic steatosis, a 2-fold increase in ceramide mass, and a 20% reduction in PC content. In an attempt to prevent NASH, LCTα(-/-) mice were either injected daily with CDP-choline or fed the high fat diet supplemented with betaine. In addition, LCTα(-/-) mice were injected with adenoviruses expressing CTα. CDP-choline injections and adenoviral expression of CTα increased hepatic PC, while dietary betaine supplementation normalized hepatic triacylglycerol but did not alter hepatic PC mass in LCTα(-/-) mice. Interestingly, none of the treatments normalized hepatic ceramide mass or fully prevented the development of NASH in LCTα(-/-) mice. These results show that normalizing the amount of hepatic PC is not sufficient to prevent NASH in LCTα(-/-) mice.
authors: University of Alberta, Edmonton, Canada.
authors: Lorissa J
authors: LJ
authors: Niebergall
authors: René L
authors: RL
authors: Jacobs
authors: Todd
authors: T
authors: Chaba
authors: Dennis E
authors: DE
authors: Vance
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001622:Betaine / Q000008:administration & dosage / Q000627:therapeutic use; D002518:Ceramides / Q000032:analysis / Q000378:metabolism; D019916:Choline-Phosphate Cytidylyltransferase / Q000172:deficiency / Q000235:genetics; D003566:Cytidine Diphosphate Choline / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D005822:Genetic Vectors / Q000008:administration & dosage; D008082:Lipotropic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D010713:Phosphatidylcholines / Q000378:metabolism*; D014280:Triglycerides / Q000032:analysis / Q000378:metabolism
chemical_list: D002518:Ceramides; D008082:Lipotropic Agents; D010713:Phosphatidylcholines; D014280:Triglycerides; D001622:Betaine; D003566:Cytidine Diphosphate Choline; D019916:Choline-Phosphate Cytidylyltransferase