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.
Keywords : phosphatidylcholine, phospholipid, methyl pool, mitochondria, S‐adenosyl methionine