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Peroxisome-Proliferator Receptor Represses Hepatic Sex Hormone-Binding Globulin Expression

Department of Obstetrics & Gynaecology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4; and Child & Family Research Institute, Vancouver, British Columbia, Canada V5Z 4H4

Address all correspondence and requests for reprints to: Geoffrey L. Hammond, Ph.D., Child & Family Research Institute, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4. E-mail: ghammond{at}cw.bc.ca.

Plasma SHBG production by the liver is influenced by its metabolic state, and hepatocyte nuclear factor-4 regulates SHBG expression in response to changes in lipogenesis. Peroxisome-proliferator receptors (PPARs) also regulate glucose homeostasis and fatty acid metabolism. The human SHBG promoter contains a PPAR-response element (PPAR-RE), and plasma SHBG levels increase in polycystic ovarian syndrome patients treated with the PPAR agonist, rosiglitazone. In addition, plasma SHBG levels are associated with a genetic polymorphism in the PPAR-2 coding sequence that alters its transcriptional activity. Therefore, we set out to determine whether PPAR influences hepatic production of SHBG by using human HepG2 hepatoblastoma cells as an in vitro model. Surprisingly, treatment of HepG2 cells with rosiglitazone reduced SHBG production and SHBG promoter activity (as assessed in a luciferase reporter gene assay) by 20–25%, whereas the PPAR antagonist, GW9662, increased both by 2- to 3-fold. The effects of PPAR agonists and antagonists on SHBG promoter activity were substantially diminished when the PPAR-RE in the SHBG promoter was mutated. A PPAR small interfering RNA also increased SHBG production by HepG2 cells as well as SHBG promoter activity, and the latter was accentuated by cotreatment with GW9662. Importantly, overexpression of a PPAR-2 Pro12 variant in HepG2 cells was more effective at reducing SHBG promoter activity, when compared with PPAR-2 Ala12, consistent with its superior PPAR-RE binding activity. We conclude that PPAR represses human SHBG expression in liver cells, and that differences in PPAR levels and activity contribute directly to variations in plasma SHBG levels.

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				D. M Selva and G. L Hammond Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4{alpha} J. Mol. Endocrinol., July 1, 2009; 43(1): 19 - 27. [Abstract] [Full Text] [PDF]