Tissue-specific induction of 17β-hydroxysteroid dehydrogenase type IV by peroxisome proliferator chemicals is dependent on the peroxisome proliferator-activated receptor α

Abstract

The 17β-hydroxysteroid dehydrogenase (17β-HSD) family of proteins regulates the levels of the active 17β-hydroxy forms of sex steroids. The expression of 17β-HSD type IV is induced by peroxisome proliferator chemicals (PPC) in rat liver. In order to characterize more generally the impact of PPC on 17β-HSD expression, we determined (1) if expression of other members of the 17β-HSD family was coordinately induced by PPC exposure, (2) the tissues in which 17β-HSD was induced by PPC, and (3) whether the induction of 17β-HSD by PPC was dependent on the peroxisome proliferator-activated receptor α (PPARα), the central mediator of PPC effects in the mouse liver. The mRNA levels of 17β-HSD I, II, and III were not altered in the liver, kidney, and testis or uterus of rats treated with PPC. The mRNA or 80 kDa full-length protein levels of 17β-HSD IV were strongly induced in liver and kidney, but not induced in adrenals, brown fat, heart, testis, and uterus of rats treated with diverse PPC. In liver and kidneys from treated rats, additional proteins of 66 kDa, 56 kDa, and 32 kDa were also induced which reacted with the anti-17β-HSD IV antibodies and were most likely proteolytic fragments of 17β-HSD IV. Treatment of mice which lack a functional form of PPARα with PPC, demonstrated that PPC-inducibility of 17β-HSD IV mRNA or the 80 kDa protein was dependent on PPARα expression in liver and kidney. Our results demonstrate that 17β-HSD IV is induced by PPC through a PPARα-dependent mechanism and support the hypothesis that exposure to PPC leads to alterations in sex steroid metabolism.