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Regulation of SREBP1c Gene Expression in Skeletal Muscle: Role of Retinoid X Receptor/Liver X Receptor and Forkhead-O1 Transcription Factor

Department of Molecular Medicine and Metabolism (Y.K., T.S., F.A., S.K., S.S., Y.O.) and Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone (S.S., Y.O.), Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan; Nutritional Science Program (S.M., A.K., O.E.), National Institute of Health and Nutrition, Tokyo 162-8636, Japan; Research Center for Advanced Science and Technology (H.A.), University of Tokyo, Tokyo 153-8904, Japan; and Departments of Medicine and Physiology and Biophysics (T.G.U.), University of Illinois College of Medicine and Jesse Brown Veterans Affairs Medical Centers, Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Osamu Ezaki M.D., Ph.D., Nutritional Science Program, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8636, Japan. E-mail: ezaki{at}nih.go.jp; or Yoshihiro Ogawa M.D, Ph.D., Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. E-mail: ogawa.mmm{at}mri.tmd.ac.jp.

Sterol regulatory element binding protein 1c (SREBP1c) is a master regulator of lipogenic gene expression in liver and adipose tissue, where its expression is regulated by a heterodimer of nuclear receptor-type transcription factors retinoid X receptor- (RXR) and liver X receptor- (LXR). Despite the potential importance of SREBP1c in skeletal muscle, little is known about the regulation of SREBP1c in that setting. Here we report that gene expression of RXR is markedly decreased by fasting and is restored by refeeding in mouse skeletal muscle, in parallel with changes in gene expression of SREBP1c. RXR or RXR, together with LXR, activate the SREBP1c promoter in vitro. Moreover, transgenic mice overexpressing RXR specifically in skeletal muscle showed increased gene expression of SREBP1c with increased triglyceride content in their skeletal muscles. In contrast, transgenic mice overexpressing the dominant-negative form of RXR showed decreased SREBP1c gene expression. The expression of Forkhead-O1 transcription factor (FOXO1), which can suppress the function of multiple nuclear receptors, is negatively correlated to that of SREBP1c in skeletal muscle during nutritional change. Moreover, transgenic mice overexpressing FOXO1 specifically in skeletal muscle exhibited decreased gene expression of both RXR and SREBP1c. In addition, FOXO1 suppressed RXR/LXR-mediated SREBP1c promoter activity in vitro. These findings provide in vivo and in vitro evidence that RXR/LXR up-regulates SREBP1c gene expression and that FOXO1 antagonizes this effect of RXR/LXR in skeletal muscle.

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