The inhibitory impact of geranylgeraniol on the differentiation of murine 3T3-F442A preadipocytes
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The use of statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, is possibly associated with insulin resistance. This potential effect of statins is presumably due to the impaired differentiation and diminished glucose utilization of adipocytes. The role of HMG-CoA reductase inhibition and mevalonate deprivation is not clear in the statin-mediated inhibition of adipocyte differentiation. There is also a need to evaluate the effect of other HMG-CoA reductase suppressors, particularly phytochemicals, on adipocyte differentiation. Mevalonate depletion is hypothesized to mediate the effect of lovastatin on adipocyte differentiation. In addition, geranylgeraniol, a diterpene shown to accelerate the degradation of HMG-CoA reductase, mimics the impact of lovastatin in adipocytes by suppressing adipocyte differentiation and adipogenic gene expression. The impact of lovastatin and geranylgeraniol, on the differentiation of murine 3T3-F442A adipocytes, were evaluated. Adipo-Red assay and oil Red O staining showed that a 7 day incubation with 1.25 - 10 umol/L lovastatin and 2.5 - 20 umol/L geranylgeraniol reduced the intracellular triglyceride content of the cells in a dose-dependant manner. Concomitantly, lovastatin and geranylgeraniol each down-regulated the expression of peroxisome proliferator-activated receptor (Ppar gamma), a key regulator of adipocyte differentiation; as analyzed by real-time qPCR. The expression of adipocyte marker genes including sterol regulatory element-binding protein 1 (SREBP1), adiponectin, leptin, and fatty acid binding protein 4 was suppressed by lovastatin. Mevalonate (500 umol/L) reversed the effect of lovastatin on intracellular triglyceride content and gene expression. The expression of SREBP1, adiponectin, leptin, fatty acid binding protein 4, fatty acid synthase, glycerol-3-phosphate dehydrogenase and glucose transporter 4 was also suppressed by geranylgeraniol. Mevalonate-derived metabolites have essential roles in promoting adipocyte differentiation and adipogenic gene expression. Dietary mevalonate suppressors may have potential as anti-adipogenic compounds.