Loss of progesterone receptor membrane component 1 promotes hepatic steatosis via the induced de novo lipogenesis

Lee, Sang Ryong; Kwon, Sun Woo; Kaya, Pelin; Lee, Young Ho; Lee, Jong Geol; Kim, Globinna; Lee, Geun‐Shik; Baek, In-Jeoung; Hong, Eui‐Ju

doi:10.1038/s41598-018-34148-6

Cited by 36 publications

(48 citation statements)

References 51 publications

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“…Progesterone receptor membrane component 1 (PGRMC1) is a novel cell surface receptor that is involved in cytochrome activities, drug metabolism, cholesterol synthesis, and steroid synthesis 10 , 11 . Recently, we found that PGRMC1 is involved in fatty liver amelioration 12 . However, it was also reported that PGRMC1 is a functional part of the GLP-1 receptor (GLP-1R) promoting insulin secretion in beta cells (β cells) 13 , 14 .…”

Section: Introductionmentioning

confidence: 99%

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

Lee

Choi

Heo

et al. 2020

Sci Rep

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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.

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Section: Introductionmentioning

confidence: 99%

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

Lee

Choi

Heo

et al. 2020

Sci Rep

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“…PGRMC1 is a member of a multi‐protein progesterone‐binding complex and its biochemical function involves binding to heme and activating P450 proteins responsible for the metabolism of drugs, hormones, and lipids . SREBP1 forms a complex with PGRMC1 and promotes lipogenesis, one of the pathways exploited by cancer cells to acquire fatty acids for increased cell metabolism . PGRMC1 has been associated with advanced‐stage disease and poor prognosis in a number of cancers, including breast, lung, and ovarian cancer .…”

Section: Introductionmentioning

confidence: 99%

Functional validation of metabolic genes that distinguish Gleason 3 from Gleason 4 prostate cancer foci

et al. 2019

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Background: Gleason grade is among the most powerful clinicopathological classification systems used to assess risk of lethal potential in prostate cancer, yet its biologic basis is poorly understood. Notably, pure low-grade cancers, comprised predominantly of Gleason pattern 3 (G3) are typically indolent, with lethal potential emerging with the progression of higher-grade Gleason patterns 4 (G4) or 5. One of the hallmarks of more aggressive cancer phenotypes is the stereotyped set of metabolic characteristics that transformed cells acquire to facilitate unregulated growth. In the present study, we profiled expression signatures of metabolic genes that are differentially expressed between G3 and G4 cancer foci and investigated the functional role of two of the profiled genes, PGRMC1 and HSD17B4, in prostate cancer cells.Methods: Gene expression profiling was conducted using 32 G3 and 32 G4 cancer foci from patients with 3+3 and ≥4+3 tumors, respectively. A 95-gene Nanostring probe set was used to probe genes associated with energy metabolism. Two out of five genes (PGRMC1 and HSD17B4) that significantly distinguish between G3 and G4 were functionally validated in vitro using established prostate cancer cells (PC3, DU145). Expression of PGRMC1 and HSD17B4 was knocked down and subsequent studies were performed to analyze cell proliferation, migration, invasion, and apoptosis. Mechanistic studies that explored the epidermal growth factor receptor (EGFR) pathway were performed by Western blot.Results: Multivariate analysis identified five metabolic genes that were differentially expressed between G3 and G4 stroma (P < .05). Functional validation studies revealed that knockdown of PGRMC1 and HSD17B4 significantly decreased cell proliferation, migration, and invasion, and increased apoptosis in PC3 and DU145 cells. Mechanistic studies showed that these effects, after PGRMC1 knockdown, were possibly mediated through alterations in downstream components of the EGFR, protein kinase B, and nuclear factor kappa-light-chain-enhancer of activated B cells pathways. Conclusion:The following study provides evidence supporting the use of metabolic genes PGRMC1 and HSD17B4 as a prognostic biomarker for the distinction between G3 and G4 prostate cancers. K E Y W O R D Sbiomarkers, functional validation, Gleason score, metabolism, prostate cancer

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“…Loss of PGRMC1 affects the SREBP-1/fatty acid homeostasis system [77], and PGRMC1 influences cell surface localization of insulin receptor and glucose transporters [26]. Chemical proteomics showed that PGRMC2 but not PGRMC1 promotes adipogenesis in 3T3-L1 preadipocytes following a gain of function interaction with a novel small molecule which displaced heme [78].…”

Section: Discussionmentioning

confidence: 99%

PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth

Thejer

Adhikary

Kaur

et al. 2020

Preprint

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Background: Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. It contains phosphorylated tyrosines which evolutionarily preceded deuterostome gastrulation and tissue differentiation mechanisms. Results: We demonstrate that manipulating PGRMC1 phosphorylation status in MIA PaCa-2 (MP) cells imposes broad pleiotropic effects. Relative to parental cells over-expressing hemagglutinin-tagged wild-type (WT) PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant (DM) exhibited reduced levels of proteins involved in energy metabolism and mitochondrial function, and altered glucose metabolism suggesting modulation of the Warburg effect. This was associated with increased PI3K/Akt activity, altered cell shape, actin cytoskeleton, motility, and mitochondrial properties. An S57A/Y180F/S181A triple mutant (TM) indicated the involvement of Y180 in PI3K/Akt activation. Mutation of Y180F strongly attenuated subcutaneous xenograft tumor growth in NOD-SCID gamma mice. Elsewhere we demonstrate altered metabolism, mutation incidence, and epigenetic status in these cells. Conclusions: Altogether, these results indicate that mutational manipulation of PGRMC1 phosphorylation status exerts broad pleiotropic effects relevant to cancer and other cell biology.

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Loss of progesterone receptor membrane component 1 promotes hepatic steatosis via the induced de novo lipogenesis

Cited by 36 publications

References 51 publications

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

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

Functional validation of metabolic genes that distinguish Gleason 3 from Gleason 4 prostate cancer foci

PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth

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