The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis

Cell Metab. 2006 May;3(5):321-31. doi: 10.1016/j.cmet.2006.03.007.

Abstract

Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are major phospholipids in mammalian membranes. In liver, PC is synthesized via the choline pathway or by methylation of PE via phosphatidylethanolamine N-methyltransferase (PEMT). Pemt(-/-) mice fed a choline-deficient (CD) diet develop rapid steatohepatitis leading to liver failure. Steatosis is observed in CD mice that lack both PEMT and multiple drug-resistant protein 2 (MDR2), required for PC secretion into bile. We demonstrate that liver failure in CD-Pemt(-/-) mice is due to loss of membrane integrity caused by a decreased PC/PE ratio. The CD-Mdr2(-/-)/Pemt(-/-) mice escape liver failure by maintaining a normal PC/PE ratio. Manipulation of PC/PE levels suggests that this ratio is a key regulator of cell membrane integrity and plays a role in the progression of steatosis into steatohepatitis. The results have clinical implications as patients with nonalcoholic steatohepatitis have a decreased ratio of PC to PE compared to control livers.

Publication types

  • Comparative Study

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Animals
  • Cell Membrane / metabolism*
  • Cell Membrane / pathology
  • Choline Deficiency / complications
  • Choline Deficiency / metabolism
  • Choline Deficiency / pathology
  • Disease Progression
  • Fatty Liver / etiology
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Hepatocytes / ultrastructure
  • Liver Failure, Acute / etiology
  • Liver Failure, Acute / metabolism*
  • Liver Failure, Acute / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphatidylcholines / metabolism*
  • Phosphatidylethanolamine N-Methyltransferase / genetics
  • Phosphatidylethanolamine N-Methyltransferase / metabolism
  • Phosphatidylethanolamines / metabolism*

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • P-glycoprotein 2
  • Phosphatidylcholines
  • Phosphatidylethanolamines
  • phosphatidylethanolamine
  • Phosphatidylethanolamine N-Methyltransferase