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150 REGULATION OF SREBP-1 EXPRESSION IN SKELETAL MUSCLE OF ZUCKER DIABETIC RATS BY FENOFIBRATE AND ROSIGLITAZONE.
  1. K. Nadeau,
  2. L. Ehlers,
  3. L. Aguire,
  4. J. E.B. Reusch,
  5. B. Draznin
  1. VA Medical Center and University of Colorado Health Sciences Center, Denver. CO

Abstract

Purpose Intramyocellular triglyceride (IMTG) content is known to be increased in states of insulin resistance and type 2 diabetes (T2DM), but the mechanism remains unclear. SREBP-1 is a transcription factor that regulates lipid synthesis, and because it is up-regulated by insulin, could mechanistically link insulin resistance and compensatory hyperinsulinemia with increased IMTG. Furthermore, medications used to treat T2DM or dyslipidemia may affect SREBP-1 and subsequently IMTG.

Methods In this study, we examined the effects of fenofibrate (FF) and rosiglitazone (Rosi) on SREBP-1 expression in skeletal muscle of 24 Zucker diabetic fatty rats (ZDF, an animal model of T2DM) and 6 age-matched controls. ZDF animals were treated with chow mixed with FF, Rosi, both drugs combined, or standard chow for approximately 25 weeks (6 in each group). Skeletal muscle (gastrocnemius) SREBP-1 expression was assessed by either RT-PCR (mRNA levels) or Western blotting (protein levels).

Results Control animals weighed significantly less than untreated ZDF (394 ± 3g vs 431 ± 5 g, p = .01). Weights were higher after treatment with Rosi (796 ± 5 g, p < .001) or Rosi/FF (642 ± 3.7g, p = .01) and lower with FF (364 ± 8 g, p = .03) than in untreated ZDF. Treatment with Rosi and Rosi/FF significantly improved glycemia (168 ± 6 mg/dL, p < .01; 223 ± 14 mg/dL, p = .02, respectively) vs untreated (481 ± 15 mg/dL, p < .01) or FF-treated rats (421 ± 13 mg/dL, p < .02). SREBP-1c mRNA was significantly higher in untreated ZDF than controls (5.7 ± 2.7 vs 1.3 ± 0.2, p = .004). Treatment of ZDF with FF significantly reduced SREBP-1 mRNA levels from 5.7 ± 2.7 to 3.0 ± 1.9 (p = .01) and SREBP-1 protein by 50% (p = .002). In contrast, treatment with Rosi failed to decrease SREBP-1 protein or mRNA levels, while Rosi/FF showed a nonsignificant trend toward lowering SREBP-1 mRNA and SREBP-1 protein.

Conclusion Skeletal muscle SREBP-1 is higher in the hyperglycemic ZDF and is reduced by treatment with FF. Rosi, despite improvement in glycemia, failed to affect SREBP-1 expression.

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