Effect of pitavastatin on apolipoprotein A-I production in HepG2 cell.
There are few reports describing the mechanism of HDL-elevating action of HMG-CoA reductase inhibitors (statins). As it is considered that the key step of HDL production is the secretion of apolipoprotein A-I (apoA-I), we investigated the effect of statins on apoA-I synthesis and secretion by HepG2 cell to elucidate the mechanism of the action. Each statin induced apoA-I expression (mRNA and protein) dose-dependently: the rank order of the apoA-I induction pitavastatin (3 microM)>simvastatin (10 microM)>atorvastatin (30 microM). The induction of apoA-I by statins disappeared with addition of mevalonate, which indicates that the effect is HMG-CoA reductase inhibition-dependent. Based on HMG-CoA reductase inhibition, pitavastatin-induced apoA-I more efficiently than simvastatin and atorvastatin. Further study revealed that pitavastatin increased ABCA1 mRNA in HMG-CoA reductase-dependent manner and that Rho and Rho kinase inhibitor (C3T and Y27632) increased apoA-I production in the HepG2 cells. These results suggest that pitavastatin efficiently increases apoA-I in the culture medium of HepG2 cells by promoting apoA-I production through inhibition of HMG-CoA reductase and suppression of Rho activity and by protecting apoA-I from catabolism through ABCA1 induction and lipidation of apoA-I.
T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T24 T25 T26 T27 T28 T29 T2 T30 T31 T32 T33 T34 T35 T36 T37 T38 T39 T3 T40 T41 T4 T5 T6 T7 T8 T9
CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-Y GENE-Y CHEMICAL GENE-N GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-N CHEMICAL GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
HMG-CoA simvastatin atorvastatin pitavastatin HMG-CoA Y27632 pitavastatin apoA-I apoA-I HMG-CoA reductase pitavastatin Rho apoA-I ABCA1 apoA-I HDL apolipoprotein A-I apoA-I apoA-I apoA-I apoA-I HMG-CoA HDL apoA-I HMG-CoA reductase HMG-CoA reductase apoA-I HMG-CoA reductase ABCA1 HMG-CoA reductase Rho Rho kinase pitavastatin apoA-I apolipoprotein A-I simvastatin atorvastatin mevalonate HMG-CoA HMG-CoA pitavastatin