Methyl-sensing nuclear receptor liver receptor homolog-1 regulates mitochondrial function in mouse hepatocytes

Authors: CHOI, SUNGWOO - Baylor College Of Medicine; DONG, BINGNING - Baylor College Of Medicine; LIN, CHIH-CHUN - Baylor College Of Medicine; HEO, MI JEONG - Baylor College Of Medicine; KIM, KANG HO - Baylor College Of Medicine; SUN, ZHEN - Baylor College Of Medicine; WAGNER, MARTIN - Universitat Graz; PUTLURI, NAGIREDDY - Baylor College Of Medicine; JAE MYOUNG, SUH - Daejeon University; WANG, MENG - Baylor College Of Medicine; MOORE, DAVID - Children'S Nutrition Research Center (CNRC)

Submitted to: Hepatology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/29/2019
Publication Date: 3/22/2020
Citation: Choi, S., Dong, B., Lin, C.J., Heo, M., Kim, K., Sun, Z., Wagner, M., Putluri, N., Jae Myoung, S., Wang, M.C., Moore, D.D. 2020. Methyl-sensing nuclear receptor liver receptor homolog-1 regulates mitochondrial function in mouse hepatocytes. Hepatology. 71(3):1055-1069. https://doi.org/10.1002/hep.30884.
DOI: https://doi.org/10.1002/hep.30884

Interpretive Summary: We previously found that the hormone receptor LRH-1 can be activated by a type of fat called phosphatidylcholine (PC). In this paper we asked whether specific PC molecules made by the liver could activate LRH-1. We found that only a subset of liver PC molecules could activate LRH-1, and that this activation improved function of liver mitochondria. This work identified a new a new mechanism for control of liver food metabolism by a fat signal that is made in the liver.

Technical Abstract: 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). 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. A PEMT–LRH-1 axis regulates mitochondrial biogenesis and beta-oxidation in hepatocytes.