The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Statin-induced inhibition of the Rho-signaling pathway activates PPARα and induces HDL apoA-I
Open accessAbstract
Statins are inhibitors of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In addition to reducing LDL cholesterol, statin treatment increases the levels of the antiatherogenic HDL and its major apolipoprotein apoA-I. Here, we investigated the molecular mechanisms of apoA-I regulation by statins. Treatment with statins increased apoA-I mRNA levels in human HepG2 hepatoma cells, and this effect was reversed by the addition of mevalonate, implicating HMG-CoA reductase as the relevant target of these drugs. Pretreatment with Actinomycin D abolished the increase of apoA-I mRNA, indicating that statins act at the transcriptional level. Indeed, statins increased the human apoA-I promoter activity in transfected cells, and we have identified a statin response element that coincides with a PPARalpha response element known to confer fibrate responsiveness to this gene. The statin effect could be abolished not only by mevalonate, but also by geranylgeranyl pyrophosphate, whereas inhibition of geranylgeranyl transferase activity or treatment with an inhibitor of the Rho GTP-binding protein family increased PPARalpha activity. Using dominant negative forms of these proteins, we found that Rho A itself mediates this response. Because cotreatment with statins and fibrates activated PPARalpha in a synergistic manner, these observations provide a molecular basis for combination treatment with statins and fibrates in coronary heart disease.
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Cites
Regulation of the mevalonate pathway
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Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism
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Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis
Nicholls, S. J., Tuzcu, E. M., Sipahi, I., Grasso, A. W., Schoenhagen, P., Hu, T., Wolski, K., Crowe, T., Desai, M. Y., Hazen, S. L., et al. (2007) · JAMA · doi:10.1001/jama.297.5.499 · Cited by 724
High-Density Lipoprotein as a Therapeutic Target: A Systematic Review
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A novel anti-inflammatory role for simvastatin in inflammatory arthritis.
Leung, B. P., Sattar, N., Crilly, A., Prach, M., McCarey, D. W., Payne, H., Madhok, R., Campbell, C., Gracie, J. A., Liew, F. Y., et al. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.3.1524 · Cited by 434
Chapman, M. J., Le Goff, W., Guerin, M., & Kontush, A. (2010) · European Heart Journal · doi:10.1093/eurheartj/ehp399 · Cited by 298
Apolipoprotein C-III: understanding an emerging cardiovascular risk factor
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An ABC of apolipoprotein C-III: a clinically useful new cardiovascular risk factor?
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Tayyeb, J. Z., Popeijus, H. E., Mensink, R. P., Konings, M. C. J. M., Mokhtar, F. B. A., & Plat, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21145088 · Cited by 74
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Metadata
- Authors
- Martin, G., Duez, H., Blanquart, C., Berezowski, V., Poulain, P., Fruchart, J.-C., Najib-Fruchart, J., Glineur, C., & Staels, B.
- Venue
- Journal of Clinical Investigation
- Published
- 2001-06-01
- Volume
- 107
- Issue
- 11
- Pages
- 1423-1432
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2109063792
- Cited by
- 417
- References
- 6
- FWCI
- 35.09
- Type
- journal article
- Language
- en
- Open access
- bronze
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
