Progesterone increases blood glucose via hepatic progesterone receptor membrane component 1 under limited or impaired action of insulin

Abstract

Hepatic gluconeogenesis is the main pathway for blood glucose maintenance activated during fasting. Retardation of insulin action, such as in diabetes mellitus, activates gluconeogenesis during the fed state. While the role of progesterone (P4) in diabetes is controversial, the P4 receptor, progesterone receptor membrane component 1 (PGRMC1), is known to stimulate pancreatic insulin secretion. We investigated the role of P4, via hepatic PGRMC1, during gluconeogenesis. The PGRMC1 binding chemical, AG-205, induced PGRMC1 monomer (25 kDa) abundance, and increased PEPCK expression and glucose production in parallel with cyclic AMP (cAMP) induction in Hep3B cells. PGRMC1-mediated cyclic AMP was inhibited by an adenylate cyclase inhibitor (MDL-12,330A). PEPCK suppression in Pgrmc1 KO hepatocyte was not observed after treatment of MDL-12,330A. PGRMC1 knockdown or overexpression systems in Hep3B cells confirmed that PGRMC1 mediates PEPCK expression via phosphorylation of cAMP-response element binding protein (CREB). CREB phosphorylation and PEPCK expression in primary hepatocytes were greater than that in PGRMC1 knock-out hepatocytes. Progesterone increased PGRMC1 expression, which induced cAMP and PEPCK induction and glucose production. In vivo, P4 suppressed gluconeogenesis following plasma insulin induction under normal conditions in a mouse model. However, P4 increased blood glucose via gluconeogenesis in parallel with increases in PGRMC1 and PEPCK expression in mice in both insulin-deficient and insulin-resistant conditions. We conclude that P4 increases hepatic glucose production via PGRMC1, which may exacerbate hyperglycaemia in diabetes where insulin action is limited.

Loss of PGRMC1 Delays the Progression of Hepatocellular Carcinoma via Suppression of Pro-Inflammatory Immune Responses

“…These phenotypic discrepancies in Pgrmc1 KO mutants may be due to the differences in model organisms, gene knockout strategy, and organ-specific roles of PGRMC1; nevertheless, it is obvious that PGRMC1 plays a critical role in female reproduction. Beside its classical function such as steroid hormone synthesis [ 26 , 27 ] and metabolic function as a non-genomic progesterone receptor [ 28 , 29 , 30 , 31 ], the relevance between Pgrmc1 and cancers has been suggested in diverse organs. One example is the role of Pgrmc1 in breast cancer [ 32 , 33 ], as Pgrmc1 has been recently identified to play important roles in the survival duration and metastasis of breast cancers in a murine PyMT model [ 34 ].…”

PGRMC Proteins Are Coming of Age: A Special Issue on the Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology

“…Zebrafish knockouts produce analogous results [ 20 ]. A separate N-terminal frameshift mutation knockout of mouse PGRMC1 has revealed roles in modulation of hepatic fatty acid synthesis [ 21 ], mammary gland development [ 22 ], and regulation of hepatic glycolysis/gluconeogenesis [ 23 ]. The PGRMC1 crystal structure has provided substantial insight into PGRMC1 biology, its probable role as a sensor of gases, such as CO and NO, and the relationship of these to the redox state of heme iron [ 24 , 25 ].…”

Progesterone receptor membrane component 1 reduces cardiac steatosis and lipotoxicity via activation of fatty acid oxidation and mitochondrial respiration

“…Previous studies have shown that progesterone receptor membrane component 1 (Pgrmc1) suppresses fatty liver development and promotes pancreatic insulin secretion 9 , 10 . Although the role of Pgrmc1 has been studied in terms of various metabolic functions, including gluconeogenesis and cholesterol synthesis 11 , 12 , it has not yet been determined whether it is involved in cardiac metabolism. Based on the previous study involving the activation of P450 proteins of PGRMC1 13 , the present study sought to investigate the relationship between Pgrmc1 expression and cardiac pathogenesis including dysfunction of mitochondrial metabolism.…”