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Statins enhance peroxisome proliferator-activated receptor γ coactivator-1α activity to regulate energy metabolism

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Abstract

Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) serves as an inducible coactivator for a number of transcription factors to control energy metabolism. Insulin signaling through Akt kinase has been demonstrated to phosphorylate PGC-1α at serine 571 and downregulate its activity in the liver. Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors that reduce cholesterol synthesis in the liver. In this study, we found that statins reduced the active form of Akt and enhanced PGC-1α activity. Specifically, statins failed to activate an S571A mutant of PGC-1α. The activation of PGC-1α by statins selectively enhanced the expression of energy metabolizing enzymes and regulators including peroxisome proliferator-activated receptor α, acyl-CoA oxidase, carnitine palmitoyl transferase-1A, and pyruvate dehydrogenase kinase 4. Importantly, a constitutively active form of Akt partially reduced the statin-enhanced gene expression. Our study thus provides a plausible mechanistic explanation for the hypolipidemic effect of statin through elevating the rate of β-oxidation and mitochondrial Kreb’s cycle capacity to enhance fatty acid utilization while reducing the rate of glycolysis.

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Acknowledgements

We sincerely thank Dr. Renke Dai, Ms. Yan Chen, and Ms. Qiong Pan for their support in rat primary hepatocyte isolation. The research is supported by grants from the National Natural Science Foundation of China #30672463, the National Basic Research Program of China (973-Program) #2006CB50390, and the Knowledge Innovation Program of the Chinese Academy of Sciences # KSCX2-YW-R-085.

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The manuscript has been seen and approved by all authors. The authors declare no conflicts of interest or competing financial interests.

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  1. Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510663, China

    Wenxian Wang & Chi-Wai Wong

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  1. Wenxian Wang
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Correspondence to Chi-Wai Wong.

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Fig. S1

Red yeast rice (a) and pure lovastatin (b) were dissolved in ethanol and analyzed by high performance liquid chromatography (HPLC) at a flow rate of 1 ml/min. Static phase was water containing 1% acetic acid (v/v), while mobile phase was methanol. Elution fractions were resolved and collected at different time points. Lovastatin was eluted at 36.6 min. The ultraviolet absorption spectrums of fraction 36.6 min of red yeast rice (c) and pure lovastatin (d) were shown when excited from 190 to 370 nm; (e) mass spectrum of 36.6 min fraction of red yeast rice and pure lovastatin using electron spray spectrometry. Based on an area under the curve analysis of HPLC fraction compared to pure lovastatin, the concentration of lovastatin in red yeast rice extract and 36.6 min fraction was estimated to be 8 and 5 mM, respectively. These were further diluted 1,000-fold in the transfection assays resulting in final concentrations of 8 and 5 μM, respectively, for the extract and 36.6 min fraction. These concentrations were highly comparable to the 10 μM statins used (DOC 826 kb)

Fig. S2

HepG2 cells were transfected with 25 ng of pGL3-basic or pGL3-ERRE reporter luciferase vector and 5 ng of pRL-tk Renilla luciferase plasmid as an internal control to detect endogenous ERR activity. Statins were added for 24 h after an overnight transfection. Luciferase and Renilla luciferase activities were measured by a Dual-Glo system from Promega. Normalized activities were shown. Fluvastatin (FLU), 10 μM, and 10 μM lovastatin (LOV) both increased ERRE promoter activities relative to control (CTL) but did not influence the activity of pGL3-basic empty vector. RLU relative light units (n = 3, single asterisk: P < 0.05, double asterisks: P < 0.01) (DOC 414 kb)

Fig. S3

HepG2 cells (a) and rat primary hepatocytes (b) were treated with dimethyl sulfoxide as a control (CTL), 10 μM fluvastatin (FLU), or 10 μM lovastatin (LOV) for 24 h and then stimulated with insulin indicated for 30 min. Total Akt and phosphorylated Akt (p-Ser473) protein levels were detected by Western analysis (upper panels). In contrast to phosphate buffered saline (PBS), Akt phosphorylation was induced by insulin but partially blocked by fluvastatin and lovastatin. The protein levels from three separated experiments were analyzed according to band intensity and quantified as relative ratio (lower panel) (n = 3, single asterisk: P < 0.05, double asterisks: P < 0.01) (DOC 567 kb)

Fig. S4

a Effects of 10 μM lovastatin on Gal4-DBD-PGC-1α wide type (WT), S571A, and T263A/S266A mutants were examined by measuring pFR-Luc and Renilla luciferase activities in cotransfected HepG2 cells. RLU relative light units (n = 3, double asterisks: P < 0.01). b Effects of 10 μM lovastatin (LOV10) on the activity of ERRα-LBD with or without the expression plasmids of PGC-1α, Myr-Akt, or PGC-1α mutant S571A. The fold inductions of LOV10 on relative luciferase activity were shown relative to vehicle control (n = 3, single asterisk: P < 0.05, double asterisks: P < 0.01) (DOC 396 kb)

Fig. S5

Gene expression was analyzed in rat primary hepatocytes using quantitative real-time polymerase chain reaction. Fold expression induced by 10 μM fluvastatin was compared with vehicle (DOC 354 kb)

Fig. S6

HepG2 cells were cultured overnight in 96-well plates and then the cultured media were supplemented with 2% bovine serum albumin, 0.5 mM palmitic acid, and 10 μM fluvastatin or dimethyl sulfoxide as a vehicle. After further incubating for 24 h, the media were transferred for β-hydroxybutyrate assay according to the manufacturer’s instructions (Cayman; n = 4, single asterisk: P < 0.01) (DOC 493 kb)

Fig. S7

β-hydroxyacyl-CoA dehydrogenase (HADH) and citrate synthase (CS) activities were measured in HepG2 cells as in “Materials and methods” section. Fold activity by 10 μM lovastatin (LOV10) was determined relative to vehicle (n = 3, single asterisk: P < 0.05, double asterisks: P < 0.01) (DOC 304 kb)

Fig. S8

The nuclear and cytosolic protein fractions in vehicle or fluvastatin (FLU)-treated HepG2 cells were extracted using Nuclear and Cytoplasmic Protein Extraction Kit (Beyotime). Of protein extracts, 30 μg was resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to polyvinylidene fluoride membrane. Western blot showed PGC-1α protein level using ECL method. NS non-specific (DOC 67 kb)

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Wang, W., Wong, CW. Statins enhance peroxisome proliferator-activated receptor γ coactivator-1α activity to regulate energy metabolism. J Mol Med 88, 309–317 (2010). https://doi.org/10.1007/s00109-009-0561-1

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