Pitavastatin induces PON1 expression through p44/42 mitogen-activated protein kinase signaling cascade in Huh7 cells.
It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors have pleiotropic effects and that human serum paraoxonase (PON1) inhibits the oxidative modification of low-density lipoprotein. We investigated the effects of pitavastatin on PON1 gene promoter activity and PON1 protein expression through the activation of mitogen-activated protein (MAP) kinase signaling cascades in cultured Huh7 cells. Both PON1 gene promoter activity and PON1 protein expression were elevated by pitavastatin stimulation. Pitavastatin phosphorylated p44/42 MAP kinase. The effects of pitavastatin on PON1 promoter activity and PON1 protein expression were attenuated by PD98059. The cotransfection of Sp1 expression vector increased PON1 promoter activity, and mithramycin suppressed pitavastatin-enhanced PON1 promoter activity. The latter activity was attenuated by cotransfection with the expression vector of sterol regulatory element-binding protein-2 (SREBP-2) with mutated p44/42 MAP kinase specific phosphorylation sites. Pitavastatin increased the Sp1-PON1 DNA complex and this effect was attenuated by PD98059. These observations suggest that pitavastatin phosphorylates p44/42 MAP kinase and then activates the transcription of PON1 gene and increases the PON1 protein expression in Huh7 cells. Furthermore, we speculate that pitavastatin affects both the phosphorylation of SREBP-2 and the Sp1 binding to PON1 DNA through the activation of p44/42 MAP kinase signaling cascade.
Arii
Kaoru
K
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan. ariik@kochi-u.ac.jp
Suehiro
Tadashi
T
Ota
Kikuko
K
Ikeda
Yukio
Y
Kumon
Yoshitaka
Y
Osaki
Fumiaki
F
Inoue
Mari
M
Inada
Syojiro
S
Ogami
Naoko
N
Takata
Hiroshi
H
Hashimoto
Kozo
K
Terada
Yoshio
Y
D043303:Aryldialkylphosphatase / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism
D004791:Enzyme Inhibitors; D011804:Quinolines; C497390:SREBF2 protein, human; D016329:Sp1 Transcription Factor; D051782:Sterol Regulatory Element Binding Protein 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; C108475:pitavastatin