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Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene.
Metabolism. 2005 Feb; 54(2):142-50.M

Abstract

Hepatic hydroxymethyl glutary coenzyme A HMG-CoA reductase inhibitors (statins) have various anti atherosclerosis pleiotropic effects that are independent of cholesterol reduction. Human serum paraoxonase 1 (PON1) is associated with high-density lipoprotein (HDL) and inhibits the oxidative modification of low-density lipoprotein (LDL). We investigated the effects of statins on PON1 gene transcription using a reporter gene assay. Promoter activity of the PON1 gene was estimated by measuring luciferase activity of plasmids with a PON1 promoter region transfected into human hepatoma HepG2 cells and human embryonic kidney (HEK) 293 cells. Pitavastatin, simvastatin, and atorvastatin each significantly increased PON1 promoter activity, and the transactivation by pitavastatin was abrogated by mevalonic acid and farnesyl pyrophosphate (FPP), however, not by geranylgeranyl pyrophosphate. Further, PON1 promoter activity was enhanced by farnesyl transferase inhibitor (FTI), but not by geranylgeranyl transferase inhibitor (GGTI). PON1 gene transcription has been reported to be dependent on Sp1 and the transactivation by pitavastatin was completely abrogated by mithramycin, an inhibitor of Sp1. Our results suggest that pitavastatin activates transcription of the PON1 gene through the FPP pathway, which may play an important role in the anti atherosclerotic effects of statins.

Authors+Show Affiliations

Department of Endocrinology, Metabolism and Nephrology, Mochi Medical School, Kochi University, Kochi 783-8505, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15690306

Citation

Ota, Kikuko, et al. "Effect of Pitavastatin On Transactivation of Human Serum Paraoxonase 1 Gene." Metabolism: Clinical and Experimental, vol. 54, no. 2, 2005, pp. 142-50.
Ota K, Suehiro T, Arii K, et al. Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene. Metabolism. 2005;54(2):142-50.
Ota, K., Suehiro, T., Arii, K., Ikeda, Y., Kumon, Y., Osaki, F., & Hashimoto, K. (2005). Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene. Metabolism: Clinical and Experimental, 54(2), 142-50.
Ota K, et al. Effect of Pitavastatin On Transactivation of Human Serum Paraoxonase 1 Gene. Metabolism. 2005;54(2):142-50. PubMed PMID: 15690306.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene. AU - Ota,Kikuko, AU - Suehiro,Tadashi, AU - Arii,Kaoru, AU - Ikeda,Yukio, AU - Kumon,Yoshitaka, AU - Osaki,Fumiaki, AU - Hashimoto,Kozo, PY - 2005/2/4/pubmed PY - 2005/3/30/medline PY - 2005/2/4/entrez SP - 142 EP - 50 JF - Metabolism: clinical and experimental JO - Metabolism VL - 54 IS - 2 N2 - Hepatic hydroxymethyl glutary coenzyme A HMG-CoA reductase inhibitors (statins) have various anti atherosclerosis pleiotropic effects that are independent of cholesterol reduction. Human serum paraoxonase 1 (PON1) is associated with high-density lipoprotein (HDL) and inhibits the oxidative modification of low-density lipoprotein (LDL). We investigated the effects of statins on PON1 gene transcription using a reporter gene assay. Promoter activity of the PON1 gene was estimated by measuring luciferase activity of plasmids with a PON1 promoter region transfected into human hepatoma HepG2 cells and human embryonic kidney (HEK) 293 cells. Pitavastatin, simvastatin, and atorvastatin each significantly increased PON1 promoter activity, and the transactivation by pitavastatin was abrogated by mevalonic acid and farnesyl pyrophosphate (FPP), however, not by geranylgeranyl pyrophosphate. Further, PON1 promoter activity was enhanced by farnesyl transferase inhibitor (FTI), but not by geranylgeranyl transferase inhibitor (GGTI). PON1 gene transcription has been reported to be dependent on Sp1 and the transactivation by pitavastatin was completely abrogated by mithramycin, an inhibitor of Sp1. Our results suggest that pitavastatin activates transcription of the PON1 gene through the FPP pathway, which may play an important role in the anti atherosclerotic effects of statins. SN - 0026-0495 UR - https://www.unboundmedicine.com/medline/citation/15690306/Effect_of_pitavastatin_on_transactivation_of_human_serum_paraoxonase_1_gene_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0026049504002732 DB - PRIME DP - Unbound Medicine ER -