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

Abstract

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.

Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis

“…Similarly, we have seen that the general mitochondrial activity (MTT), as well as the ATP concentration, is drastically reduced in 3d2-treated cells. Indeed, loss of LRH-1 has been very recently related to reduced mitochondrial function and ATP production in hepatocytes 22 . Thus, it is very likely that LRH-1 inhibition results in reduced or altered metabolism in LPS-stimulated macrophages, which impairs downstream effector functions, such as the secretion of pro-inflammatory cytokines.…”

“…4e). Indeed, besides regulating cell cycle progression and proliferation, LRH-1 has been involved in the control of mitochondrial function and metabolic processes [1][2][3]21,22 . In line with this notion, RAW 264.7 cells exposed to increasing concentrations of 3d2 showed a significant decrease in cellular ATP levels ( Fig.…”

Nuclear‐mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog‐1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer

“…Most importantly, LRH-1 stimulates mitochondrial energy metabolism by increasing mitochondrial mass and induction of mitochondrial metabolic target genes that promote increased lipid, amino acid, and glucose utilization. 56,121,130,135 LRH-1 thereby likely contributes to an indispensable metabolic reprogramming that ensures fulfillment of the increased energy demand concomitant with the synthesis of proteins that are vital for their rapid proliferation and survival of tumor cells. Elevated LRH-1 activity promoting diverse, but mainly mitochondrial processes, is clearly beneficial for the viability of malignant cells.…”

“…Even more intriguing is the finding that activation of LRH-1 increases the expression of PGC-1α. 130 This suggests a positive feedback loop, in which LRH-1 induces its own coactivator to directly enhance mitochondrial biomass and function, a process that once deregulated likely contributes to tumorigenesis. In this regard, it is interesting that also the LRH-1 target gene c-Myc contributes to an increase in mitochondrial mass.…”

“…LRH-1 thus also seems to be a critical regulator of mitochondrial FAO, which could contribute to the metabolic transformation, survival, and apoptosis resistance in certain cancer types. 130 As a result of the Warburg effect and the limited availability of pyruvate that feeds into mitochondrial metabolism, cancer cells rely on alternative substrates that feed into the TCA cycle, and are in this context particularly depend on glutamine. Despite fueling the TCA cycle, glutamine serves as an important building block for the synthesis of amino acids, nucleotides, lipids, and glutathione.…”