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.
Tokyo New Drug Research Laboratories I, Kowa Company Ltd., Tokyo, Japan. hyamazk@kowa.ac.jp
Takashi
T
Maejima
H
H
Yamazaki
T
T
Aoki
T
T
Tamaki
F
F
Sato
M
M
Kitahara
Y
Y
Saito
D016632:Apolipoprotein A-I / Q000737:chemistry*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D054460:rho-Associated Kinases
D016632:Apolipoprotein A-I; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL; D047493:PPAR alpha; D011804:Quinolines; D012333:RNA, Messenger; D012313:RNA; D006903:Hydroxymethylglutaryl CoA Reductases; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C108475:pitavastatin