Effect of pitavastatin on apolipoprotein A-I production in HepG2 cell

• DOI: 10.1016/j.bbrc.2004.09.122
• Publication Date: 2004-10-05T15:08:50Z
• Authors: Takashi Maejima; H. Yamazaki; T. Aoki; T. Tamaki; F. Sato; M. Kitahara; Y. Saito
• Keywords: rho-Associated Kinases; Time Factors; Apolipoprotein A-I; Dose-Response Relationship, Drug; Intracellular Signaling Peptides and Proteins; Enzyme-Linked Immunosorbent Assay; Protein Serine-Threonine Kinases; Lipid Metabolism; Cell Line; 03 medical and health sciences; 0302 clinical medicine; Quinolines; Humans; RNA; Hydroxymethylglutaryl CoA Reductases; PPAR alpha; RNA, Messenger; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins, HDL

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.