Abstract
Progesterone receptor membrane associated component 1 (PGRMC1) exhibits haem-dependent dimerization on cell membrane and binds to EGF receptor and cytochromes P450 to regulate cancer proliferation and chemoresistance. However, its physiological functions remain unknown. Herein, we demonstrate that PGRMC1 is required for adipogenesis, and its expression is significantly enhanced by insulin or thiazolidine, an agonist for PPARγ. The haem-dimerized PGRMC1 interacts with low-density lipoprotein receptors (VLDL-R and LDL-R) or GLUT4 to regulate their translocation to the plasma membrane, facilitating lipid uptake and accumulation, and de-novo fatty acid synthesis in adipocytes. These events are cancelled by CO through interfering with PGRMC1 dimerization. PGRMC1 expression in mouse adipose tissues is enhanced during obesity induced by a high fat diet. Furthermore, adipose tissue-specific PGRMC1 knockout in mice dramatically suppressed high-fat-diet induced adipocyte hypertrophy. Our results indicate a pivotal role of PGRMC1 in developing obesity through its metabolic regulation of lipids and carbohydrates in adipocytes.
Highlights
Progesterone receptor membrane associated component 1 (PGRMC1) exhibits haemdependent dimerization on cell membrane and binds to EGF receptor and cytochromes P450 to regulate cancer proliferation and chemoresistance
We previously explored that haem-dependent dimerization of PGRMC1 accounts for a functional complex that binds to EGF receptor (EGFR) or to cytochromes P450 to regulate cancer proliferation and chemoresistance, respectively[23]
We have previously shown that physiological actions of carbon monoxide (CO) derived from haem oxygenase (HO)[36,37,38,39], and PGRMC1 accounts for a receptor of CO which interferes with the haem-stacking dimerization of PGRMC123, raising a possibility that CO interferes with the PGRMC1-mediated lipid and glucose uptake in the adipocyte
Summary
Progesterone receptor membrane associated component 1 (PGRMC1) exhibits haemdependent dimerization on cell membrane and binds to EGF receptor and cytochromes P450 to regulate cancer proliferation and chemoresistance. D Analyses of protein expressions in 3T3L1 control cells during differentiation by western blotting using antibodies against PGRMC1, PPARγ, FABP4, or GAPDH. We confirmed that the reporter activities of the PGRMC1 promoter (−1695/+1-PGRMC1-Luc) or the PPRE x3-containing construct were significantly elevated by the addition of TZD in 293T cells co-transfected with the PPARγ expression vector (Supplementary Fig. 3).
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