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

Abstract

Liver receptor homolog-1 (LRH-1, NR5A2) is an orphan nuclear receptor with widespread activities in the regulation of development, stemness, metabolism, steroidogenesis, and proliferation. Many of the LRH-1-regulated processes target the mitochondria and associated activities. While under physiological conditions, a balanced LRH-1 expression and regulation contribute to the maintenance of a physiological equilibrium, deregulation of LRH-1 has been associated with inflammation and cancer. In this review, we discuss the role and mechanism(s) of how LRH-1 regulates metabolic processes, cell survival, and cancer in a nuclear-mitochondrial crosstalk, and evaluate its potential as a pharmacological target.

LRH-1/NR5A2 regulates the PTGS2-PGE2-PTGER1 signalling axis contributing to islet survival and antidiabetic actions of the agonist BL001

“…This complex networking is further underlined by findings that PGE2 stimulates LRH-1/NR5A2 expression levels indicating a feedforward mechanism between the nuclear receptor and PTGS2 3 .…”

“…Of particular interest, is the liver receptor homolog 1 (LRH-1, also known as NR5A2) that belongs to the NR5A family of nuclear receptors 2 . LRH-1/NR5A2 is highly expressed in the liver, intestine and pancreas, whereas lower expression levels are detected in the brain and immune cell types such as macrophages and T cells 3 . LRH-1/NR5A2 is essential for embryonic development, while in adult it regulates key metabolic pathways.…”

“…Notwithstanding, other studies contend that inhibition or deletion of PTGS2 shield human islet against cytokine-mediated beta cell dismay 19 . Interestingly, in breast cancer cells the downstream metabolic pathway product of PTGS2/COX2, prostaglandin E2 (PGE2), induces LRH-1 mRNA expression by recruitment of multiple transcriptional activators to the LRH-1 promoter 3 . Taking all together, whether the axis LRH1/PTGS2 is of importance in pancreatic beta cells remains to be clarified.…”

NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway contributing to pancreatic islet survival and function

“…Of particular interest is the liver receptor homolog 1 (LRH-1, also known as NR5A2) that belongs to the NR5A family of nuclear receptors ( Fayard et al., 2004 ). LRH-1/NR5A2 is highly expressed in the liver, intestine, and pancreas, whereas lower expression levels are detected in the brain and immune cell types such as macrophages and T cells ( Michalek and Brunner, 2021 ). LRH-1/NR5A2 is essential for embryonic development, whereas in adults it regulates key metabolic pathways.…”

“…Notwithstanding, other studies contend that inhibition or deletion of PTGS2 shields the human islet against cytokine-mediated beta cell dismay ( Ma et al., 2017 ). Interestingly, in breast cancer cells, the downstream metabolic pathway product of PTGS2/COX2—prostaglandin E2 (PGE2)—induces LRH-1 mRNA expression by recruitment of multiple transcriptional activators to the LRH-1 promoter ( Michalek and Brunner, 2021 ). Taken together, whether the axis LRH1/PTGS2 is of importance in pancreatic beta cells remains to be clarified.…”