Phosphatidylethanolamine N-methyltransferase (PEMT) is an important
enzyme in hepatic
phosphatidylcholine (PC) biosynthesis. Pemt-/- mice fed a high-fat diet are protected from
obesity and whole-body
insulin resistance. However, Pemt-/- mice develop severe
nonalcoholic steatohepatitis (NASH). Because NASH is often associated with hepatic
insulin resistance, we investigated whether the increased
insulin sensitivity in Pemt-/- mice was restricted to nonhepatic tissues or whether the liver was also
insulin sensitive. Strikingly, the livers of Pemt-/- mice compared with those of Pemt+/+ mice were not
insulin resistant, despite elevated levels of hepatic
triacylglycerols and
diacylglycerols, as well as increased hepatic
inflammation and
fibrosis. Endogenous
glucose production was lower in Pemt-/- mice under both basal and hyperinsulinemic conditions. Experiments in primary hepatocytes and
hepatoma cells revealed improved
insulin signaling in the absence of PEMT, which was not due to changes in
diacylglycerols,
ceramides, or
gangliosides. On the other hand, the
phospholipid composition in hepatocytes seems critically important for
insulin signaling such that lowering the PC:
phosphatidylethanolamine (PE) ratio improves
insulin signaling. Thus, treatments to reduce the PC:PE ratio in liver may protect against the development of hepatic
insulin resistance.-Van der Veen, J. N., Lingrell, S., McCloskey, N., LeBlond, N. D., Galleguillos, D., Zhao, Y. Y., Curtis, J. M., Sipione, S., Fullerton, M. D., Vance, D. E., Jacobs, R. L. A role for
phosphatidylcholine and
phosphatidylethanolamine in hepatic
insulin signaling.