Menaquinone-4 enhances testosterone production in rats and testis-derived tumor cells.

Abstract

BACKGROUND:

Vitamin K is essential for the posttranslational modification of various Gla proteins. Although it is widespread in several organs, including the testis, the function of vitamin K in these organs is not well characterized. In this study, we investigated the function of vitamin K in the testis and analyzed its role in steroidogenesis.

METHODS:

Eight-week-old male Wistar rats were fed a diet supplemented with menaquinone-4 (MK-4, 75 mg/kg diet), one of the predominant K₂ vitamins present in the testis, for 5 weeks. In vivo testosterone levels of the rats' plasma and testes were measured by enzyme-linked immunosorbent assay, and in vitro testosterone levels of testis-derived tumor cells (I-10 cells) maintained in Ham's F-10 medium with 10% fetal bovine serum were measured following treatment with MK-4 (0 to 100 μM) at several time points. Testosterone and cellular protein levels were analyzed with respect to their effects on steroidogenesis.

RESULTS:

Testosterone levels in the plasma and testes of MK-4-fed rats were significantly increased compared to those of control rats, with no obvious differences in plasma luteinizing hormone levels. Secreted testosterone levels from I-10 cells were elevated by MK-4, but not by vitamin K₁, in a dose-dependent manner independent of cAMP treatment. Western blot analysis revealed that expression of CYP11A, the rate-limiting enzyme in steroidogenesis, and phosphorylation levels of protein kinase A (PKA) and the cAMP response element-binding protein were all stimulated by the presence of MK-4. Enhancement of testosterone production was inhibited by H89, a specific inhibitor of PKA, but not by warfarin, an inhibitor of γ-glutamylcarboxylation.

CONCLUSIONS:

MK-4 stimulates testosterone production in rats and testis-derived tumor cells via activation of PKA. MK-4 may be involved in steroidogenesis in the testis, and its supplementation could reverse the downregulation of testosterone production in elders.

• Authors: Asagi Ito, Hitoshi Shirakawa, Naofumi Takumi, Yoshihiko Minegishi, Ai Ohashi, Zakir H Howlader, Yusuke Ohsaki, Toshiro Sato, Tomoko Goto, Michio Komai
• Journal: Lipids in health and disease (Lipids Health Dis) Vol. 10 Pg. 158 (Sep 13 2011) ISSN: 1476-511X [Electronic] England
• PMID: 21914161 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic AMP Response Element-Binding Protein
• Protein Kinase Inhibitors
• Vitamin K 2
• menatetrenone
• Testosterone
• Vitamin K 1
• Cholesterol Side-Chain Cleavage Enzyme
• Cyclic AMP-Dependent Protein Kinases
• Carbon-Carbon Ligases
• glutamyl carboxylase

Topics

• Animals
• Carbon-Carbon Ligases (antagonists & inhibitors)
• Cell Line, Tumor
• Cholesterol Side-Chain Cleavage Enzyme (metabolism)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors, chemistry, metabolism)
• Leydig Cells (drug effects, metabolism)
• Liver (drug effects, metabolism)
• Male
• Mice
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Protein Processing, Post-Translational (drug effects)
• Rats
• Rats, Wistar
• Specific Pathogen-Free Organisms
• Testis (drug effects, metabolism)
• Testosterone (blood, metabolism)
• Tissue Distribution
• Up-Regulation (drug effects)
• Vitamin K 1 (antagonists & inhibitors, metabolism)
• Vitamin K 2 (analogs & derivatives, pharmacokinetics, pharmacology)