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

Authors

Sungwoo Choi
Bingning Dong
Chih-Chun Janet Lin
Mi Jeong Heo
Kang Ho Kim
Zhen Sun
Martin Wagner
Nagireddy Putluri
Jae Myoung Suh
Meng C Wang
David D Moore

Publication Date

3-1-2020

Journal

Hepatology

DOI

10.1002/hep.30884

PMID

31355949

PMCID

PMC6987012

PubMedCentral® Posted Date

3-1-2021

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Hep G2 Cells, Hepatocytes, Humans, Male, Mice, Mitochondria, Oxidation-Reduction, Phosphatidylethanolamine N-Methyltransferase, Receptors, Cytoplasmic and Nuclear, S-Adenosylmethionine, phosphatidylcholine, phospholipid, methyl pool, mitochondria, S-adenosyl methionine

Abstract

Liver receptor homologue-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 via the Kennedy pathway, or trimethylation of phosphatidylethanolamine via Phosphatidylethanolamine N-methyl Transferase (PEMT). 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 ATP 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. Conclusion: A PEMT – LRH-1 axis regulates mitochondrial biogenesis and beta-oxidation in hepatocytes.