HDL promotes adiponectin gene expression via the CAMKK/CAMKIV pathway

in Journal of Molecular Endocrinology
Authors:
Toshihiro KobayashiDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

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Hitomi ImachiDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

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Kensaku FukunagaDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

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Jingya LyuDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

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Seisuke SatoDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

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Takanobu SahekiDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

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Tomohiro IbataDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

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Mari MatsumotoDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

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Salimah B JaparDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

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Koji MuraoDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

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Correspondence should be addressed to K Murao: mkoji@med.kagawa-u.ac.jp
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Adiponectin (APN) is an adipokine that protects against diabetes and atherosclerosis. High-density lipoprotein (HDL) mediates reverse cholesterol transport, which also protects against atherosclerosis. In this process, the human homolog of the B class type I scavenger receptor (SR-BI/CLA-1) facilitates the cellular uptake of cholesterol from HDL. The level of circulating APN is positively correlated with the serum level of HDL-cholesterol. In this study, we investigated whether HDL stimulates the gene expression of APN through the Ca2+/calmodulin (CaM)-dependent protein kinase IV (CaMKIV) cascade. APN expression was examined using real-time PCR and western blot analysis in 3T3-L1 cells incubated with HDL. CaMKIV activity was assessed by the detection of activation loop phosphorylation (at Thr196 residue), and the effect of the constitutively active form, CaMKIVc, on APN promoter activity was investigated. Our results showed that HDL stimulated APN gene expression via hSR-BI/CLA-1. Furthermore, we explored the signaling pathways by which HDL stimulated APN expression in 3T3-L1 cells. The stimulation of APN gene expression by HDL appears to be mediated by CaMKK, as STO-609, a specific inhibitor of CaMKK2, prevents this effect. We revealed that CaMKIVc increased APN gene transcriptional activity, and the CaMKIV-dominant negative mutant blocked the effect of HDL on APN promoter activity. Finally, knockdown of hSR-BI/CLA-1 also canceled the effect of HDL on APN gene expression. These results suggest that HDL has an important role to improve the function of adipocytes by activating hSR-BI/CLA-1, and CaMKK/CaMKIV pathway is conceivable as one of the signaling pathways of this activation mechanism.

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