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Beneficial direct adipotropic actions of pitavastatin in vitro and their manifestations in obese mice

      Abstract

      Objective

      Prevention of cardiovascular complications in obese patients frequently includes statin administration for coexisting dyslipidemia. Herein, we investigated the impacts of pitavastatin at clinically relevant doses on adipose dysfunction and insulin resistance.

      Methods

      We treated 3T3-L1 preadipocytes with 10–100 ng/ml pitavastatin from initiation of differentiation (Day 0) to Day 8 (differentiation/maturation phase) or from Day 8 to Day 16 (post-maturation phase). Subsequently, we administered pitavastatin (6.2 mg/day/kg) to 7-week-old female KKAy mice for 6 weeks; untreated KKAy mice served as obese controls.

      Results

      Pitavastatin impaired neither lipogenesis nor adiponectin expression during the differentiation/maturation phase. During the post-maturation phase, pitavastatin prevented excessive triglyceride accumulation, which was associated with attenuated glucose transporter-4 expression, and dose-dependently upregulated hormone-sensitive lipase expression. Decrements in the adiponectin/plasminogen activator-1 ratio were also dose-dependently inhibited. In KKAy mice, Coulter counter analyses revealed that pitavastatin treatment significantly decreased (by 16.8%) the frequency of hypertrophic adipocytes (>150 μm in diameter) in parametrial adipose pads, of which total weight remained unaltered. Correspondingly, plasma adiponectin was significantly higher in pitavastatin-treated KKAy mice than in the untreated KKAy mice (12.5 ± 3.8 μg/ml vs. 8.3 ± 1.5 μg/ml, p < 0.05). Moreover, the area under the time–glucose curve after intraperitoneal insulin was decreased by 16% in pitavastatin-treated KKAy mice (p < 0.05 vs. untreated controls).

      Conclusions

      Pitavastatin did not impair differentiation/maturation of preadipocytes and prevented their deterioration with hypertrophy after maturation at clinical concentrations in vitro. These effects likely contributed to improved insulin sensitivity, in an obese model, via prevention of adipocyte hypertrophy and adipocytokine dysregulation.

      Keywords

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      References

        • Freeman D.J.
        • Norrie J.
        • Sattar N.
        • et al.
        Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.
        Circulation. 2001; 103: 357-362
        • Yu Y.
        • Ohmori K.
        • Chen Y.
        • et al.
        Effects of pravastatin on progression of glucose intolerance and cardiovascular remodeling in a type II diabetes model.
        J Am Coll Cardiol. 2004; 44: 904-913
        • Nakata M.
        • Nagasaka S.
        • Kusaka I.
        • Matsuoka H.
        • Ishibashi S.
        • Yada T.
        Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control.
        Diabetologia. 2006; 49: 1881-2192
        • Ishikawa M.
        • Namiki A.
        • Kubota T.
        • et al.
        Effect of pravastatin and atorvastatin on glucose metabolism in non-diabetic patients with hypercholesterolemia.
        Intern Med. 2006; 45: 51-55
        • Chen Y.
        • Ohmori K.
        • Mizukawa M.
        • et al.
        Differential impact of atorvastatin vs pravastatin on progressive insulin resistance and left ventricular diastolic dysfunction in a rat model of type II diabetes.
        Circ J. 2007; 71: 144-152
        • Sugiyama S.
        • Fukushima H.
        • Kugiyama K.
        • et al.
        Pravastatin improved glucose metabolism associated with increasing plasma adiponectin in patients with impaired glucose tolerance and coronary artery disease.
        Atherosclerosis. 2007; 194: e43-51
        • Takagi T.
        • Matsuda M.
        • Abe M.
        • et al.
        Effect of pravastatin on the development of diabetes and adiponectin production.
        Atherosclerosis. 2008; 196: 114-121
        • Takaguri A.
        • Satoh K.
        • Itagaki M.
        • Tokumitsu Y.
        • Ichihara K.
        Effects of atorvastatin and pravastatin on signal transduction related to glucose uptake in 3T3L1 adipocytes.
        J Pharmacol Sci. 2008; 107: 80-89
        • Yamauchi T.
        • Kamon J.
        • Waki H.
        • et al.
        The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.
        Nat Med. 2001; 7: 941-946
        • Kadowaki T.
        • Hara K.
        • Yamauchi T.
        • Terauchi Y.
        • Tobe K.
        • Nagai R.
        Molecular mechanism of insulin resistance and obesity.
        Exp Biol Med (Maywood). 2003; 228: 1111-1117
        • Maeda N.
        • Shimomura I.
        • Kishida K.
        • et al.
        Diet-induced insulin resistance in mice lacking adiponectin/ACRP30.
        Nat Med. 2002; 8: 731-737
        • Okamoto T.
        • Okamoto Y.
        • Kihara S.
        • et al.
        Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice.
        Circulation. 2002; 106: 2767-2770
        • Aleci M.C.
        • Juhan-Vague I.
        PAI-1 and the metabolic syndrome. Links, causes, and consequences.
        Atheroscler Thromb Vasc Biol. 2006; 26: 2200-2207
        • Mäuser W.
        • Perwitz N.
        • Meier B.
        • Fasshauer M.
        • Klein J.
        Direct adipotropic actions of atorvastatin: differentiation state-dependent induction of apoptosis, modulation of endocrine function, and inhibition of glucose uptake.
        Eur J Pharmacol. 2007; 564: 37-46
        • Laumen H.
        • Skurk T.
        • Hauner H.
        The HCG-CoA reductase inhibitor rosuvastatin inhibits Plasminogen activator inhibitor-1 expression and secretion in human adipocytes.
        Atherosclerosis. 2008; 196: 565-573
        • Hiro T.
        • Kimura T.
        • Morimoto T.
        • et al.
        Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome: a multicenter randomized trial evaluated by volumetric intravascular ultrasound using pitavastatin versus atorvastatin (JAPAN-ACS).
        J Am Coll Cardiol. 2009; 54: 293-302
        • Nomura S.
        • Shouzu A.
        • Omoto S.
        • et al.
        Correlation between adiponectin and reduction of cell adhesion molecules after pitavastatin treatment in hyperlipidemic patients with type 2 diabetes mellitus.
        Thromb Res. 2008; 122: 39-45
        • Nicholson A.C.
        • Hajjar D.P.
        • Zhou X.
        • He W.
        • Gotto Jr., A.M.
        • Han J.
        Anti-adipogenic action of pitavastatin occurs through the coordinate regulation of PPARgamma and Pref-1 expression.
        Br J Pharmacol. 2007; 151: 807-815
        • Lv H.
        • Sun J.G.
        • Wang G.J.
        • et al.
        Determination of pitavastatin in human plasma via HPLC-ESI-MS/MS and subsequent application to a clinical study in healthy Chinese volunteer.
        Clin Chim Acta. 2007; 386: 25-30
        • Ferrari M.
        • Fornasiero M.C.
        • Isetta A.M.
        MTT colorimetric assay for testing macrophage cytotoxic activity in vitro.
        J Immunol Methods. 1990; 131: 165-172
        • Fan W.
        • Boston B.A.
        • Kesterson R.A.
        • Hruby V.J.
        • Cone R.D.
        Role of melanocortinergic neurons in feeding and the agouti obesity syndrome.
        Nature. 1997; 385: 165-168
        • Sakai T.
        • Sakaue H.
        • Nakamura T.
        • et al.
        Skp2 controls adipocyte proliferation during the development of obesity.
        J Biol Chem. 2007; 282: 2038-2046
        • Hirsch J.
        • Gallian E.
        Methods for the determination of adipose cell size in man and animals.
        J Lipid Res. 1968; 9: 110-119
        • Gonzales A.M.
        • Orland R.A.
        Role of adipocyte-derived lipoprotein lipase in adipocyte hypertrophy.
        Nutr Metab (Lond). 2007; 4: 22
        • Sakaeda T.
        • Fujino H.
        • Komoto C.
        • et al.
        Effects of acid and lactone forms of eight HMG-CoA reductase inhibitors on CYP-mediated metabolism and MDR1-mediated transport.
        Pharmaceut Res. 2006; 23: 506-512
        • Steppan C.M.
        • Bailey S.T.
        • Bhat S.
        • et al.
        The hormone resistin links obesity to diabetes.
        Nature. 2001; 409: 307-312
        • Maebuchi M.
        • Machidori M.
        • Urada R.
        • et al.
        Low resistin level in adipose tissue and serum in high-fat fed mice and genetically obese mice: development of an ELISA system for quantification of resistin.
        Arch Biochem Biophys. 2003; 416: 164-170
        • Yagi S.
        • Aihara K.
        • Ikeda Y.
        • et al.
        Pitavastatin, an HMG-CoA reductase inhibitor, exerts eNOS-independent protective actions against angiotensin II induced cardiovascular remodeling and renal insufficiency.
        Circ Res. 2008; 102: 68-76
        • Furukawa S.
        • Fujita T.
        • Shimabukuro M.
        • et al.
        Increased oxidative stress in obesity and its impact on metabolic syndrome.
        J Clin Invest. 2004; 114: 1752-1761