Methyl-Sensing Nuclear Receptor Liver Receptor Homolog-1 Regulates Mitochondrial Function in Mouse Hepatocytes

Hepatology. 2020 Mar;71(3):1055-1069. doi: 10.1002/hep.30884. Epub 2019 Dec 23.


Background and aims: Liver receptor homolog-1 (LRH-1; NR5A2) is a nuclear receptor that regulates metabolic homeostasis in the liver. Previous studies identified phosphatidylcholines as potential endogenous agonist ligands for LRH-1. In the liver, distinct subsets of phosphatidylcholine species are generated by two different pathways: choline addition to phosphatidic acid through the Kennedy pathway and trimethylation of phosphatidylethanolamine through phosphatidylethanolamine N-methyl transferase (PEMT).

Approach and results: Here, we report that a PEMT-LRH-1 pathway specifically couples methyl metabolism and mitochondrial activities in hepatocytes. We show that the loss of Lrh-1 reduces mitochondrial number, basal respiration, beta-oxidation, and adenosine triphosphate production in hepatocytes and decreases expression of mitochondrial biogenesis and beta-oxidation genes. In contrast, activation of LRH-1 by its phosphatidylcholine agonists exerts opposite effects. While disruption of the Kennedy pathway does not affect the LRH-1-mediated regulation of mitochondrial activities, genetic or pharmaceutical inhibition of the PEMT pathway recapitulates the effects of Lrh-1 knockdown on mitochondria. Furthermore, we show that S-adenosyl methionine, a cofactor required for PEMT, is sufficient to induce Lrh-1 transactivation and consequently mitochondrial biogenesis.

Conclusions: A PEMT-LRH-1 axis regulates mitochondrial biogenesis and beta-oxidation in hepatocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Hep G2 Cells
  • Hepatocytes / metabolism*
  • Humans
  • Male
  • Mice
  • Mitochondria / physiology*
  • Oxidation-Reduction
  • Phosphatidylethanolamine N-Methyltransferase / physiology*
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • S-Adenosylmethionine / metabolism
  • S-Adenosylmethionine / pharmacology


  • Nr5a2 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • S-Adenosylmethionine
  • PEMT protein, mouse
  • Phosphatidylethanolamine N-Methyltransferase