The lipid and non-lipid effects of statins

Wierzbicki, Anthony S.; Poston, Robin N.; Ferro, Albert

doi:10.1016/s0163-7258(03)00055-x

Cited by 224 publications

(146 citation statements)

References 150 publications

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“…In addition to their effects on LDL-C, statins have antiinflammatory properties [13,14], as shown by significant reductions in hsCRP levels that appear to be unrelated to the magnitude of LDL-C reduction [15][16][17][18]. Statins are highly effective in reducing the risk of cardiovascular events in both primary and secondary prevention, to a degree that is greater than predicted on the basis of LDL-C lowering alone.…”

Section: Introductionmentioning

confidence: 99%

Effect of atorvastatin on circulating hsCRP concentrations: A sub-study of the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study

Gensini¹,

Gori²,

Dilaghi³

et al. 2010

International Journal of Cardiology

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Background: Elevated C-reactive protein (CRP) concentration is a risk factor for cardiovascular events that may add prognostic information. Statin treatment is associated with significant reductions in CRP concentrations, which appear to be unrelated to the magnitude of LDL-cholesterol reduction. We investigated the effect of atorvastatin, across its dose range, on high sensitivity (hs)CRP in subjects at high cardiovascular risk. Methods: ACTFAST was a 12 week, prospective, multicenter, open-label trial in which high-risk subjects were assigned a starting dose of atorvastatin (10,20,40 Results: At baseline, ST subjects had significantly lower hsCRP levels than SF subjects (ST group 2.31, 95% CI 2.15, 2.48 mg/L vs. SF group 3.16, 95% CI 2.98, 3.34 mg/L, p b 0.05). In the SF group, atorvastatin 10 to 80 mg significantly (p b 0.01) reduced hsCRP levels in a dose dependent-manner. In ST group, additional hsCRP reductions were observed over the statin used at baseline, which were not dosedependent. Atorvastatin significantly decreased hsCRP concentrations in subjects with or without diabetes or the metabolic syndrome. Conclusions: Atorvastatin treatment at different doses, particularly 80 mg, significantly reduced hsCRP serum concentrations. This reduction was observed in both SF and ST groups and was independent of the presence of metabolic syndrome and/or diabetes. The beneficial effect of atorvastatin was evident at 6 weeks, supporting the practice of early introduction of higher doses of atorvastatin in high-risk patients.

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Section: Introductionmentioning

confidence: 99%

Effect of atorvastatin on circulating hsCRP concentrations: A sub-study of the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study

Gensini¹,

Gori²,

Dilaghi³

et al. 2010

International Journal of Cardiology

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“…A broader hypothesis followed naturally: that statins might have general antiinflammatory and/or immunomodulatory effects. Research over the last 10 years has elucidated a number of mechanisms by which statins may exert antiinflammatory effects (7,11). In this article, we review the mechanisms of the action of statins, and the specific signaling pathways they modulate.…”

Section: Introductionmentioning

confidence: 99%

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

Abeles

Pillinger

2006

Arthritis & Rheumatism

134

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“…Statins also increase, at least in part via a PPAR␣-dependent mechanism (2), the level of high density lipoproteins (3,4). As a consequence, statins improve the blood cholesterol profile and markedly reduce cardiovascular mortality and morbidity in dyslipidemic patients (5)(6)(7). Statins also influence plasma TG and NEFA levels in rats and humans (4, 8 -11) through mechanisms not yet fully elucidated.…”

mentioning

confidence: 99%

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

Landrier

Thomas

Grober

et al. 2004

Journal of Biological Chemistry

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Statins are drugs widely used in humans to treat hypercholesterolemia. Statins act by inhibiting cholesterol synthesis resulting in the activation of the transcription factor sterol-responsive element-binding protein-2 that controls the expression of genes involved in cholesterol homeostasis. Statin therapy also decreases plasma triglyceride and non-esterified fatty acid levels, but the mechanism behind this effect remains more elusive. Liver fatty acid-binding protein (L-FABP) plays a role in the influx of long-chain fatty acids into hepatocytes. Here we show that L-FABP is a target for statins. In rat hepatocytes, simvastatin treatment induced L-FABP mRNA levels in a dose-dependent manner. Moreover, L-FABP promoter activity was induced by statin treatment. Progressive 5 -deletion analysis revealed that the peroxisome proliferator-activated receptor (PPAR)-responsive element located at position ؊67/؊55 was responsible for the statin-mediated transactivation of the rat L-FABP promoter. Moreover, treatment with simvastatin and the PPAR␣ agonist Wy14,649 resulted in a synergistic induction of L-FABP expression (mRNA and protein) in rat Fao hepatoma cells. This effect was also observed in vivo in wild-type mice but not in PPAR␣-null animals demonstrating the direct implication of PPAR␣ in L-FABP regulation by statin treatment. Statin treatment resulted in a rise in PPAR␣ mRNA levels both in vitro and in vivo and activated the mouse PPAR␣ promoter in a reporter assay. Altogether, these data demonstrate that L-FABP expression is up-regulated by statins through a mechanism involving PPAR␣. Moreover, PPAR␣ might be a statin target gene. These effects might contribute to the triglyceride/non-esterified fatty acid-lowering properties of statins.Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. The resulting lower intracellular cholesterol concentration after statin treatment leads to a proteolytic activation of the transcription factor sterol responsive element-binding protein-2 (SREBP-2), 1 which up-regulates several genes controlling cholesterol homeostasis, including the LDL receptor (LDLr) (1). Induction of LDLr in the liver enhances clearance of circulating LDL resulting in decreased plasma LDL-cholesterol levels. Statins also increase, at least in part via a PPAR␣-dependent mechanism (2), the level of high density lipoproteins (3, 4). As a consequence, statins improve the blood cholesterol profile and markedly reduce cardiovascular mortality and morbidity in dyslipidemic patients (5-7). Statins also influence plasma TG and NEFA levels in rats and humans (4, 8 -11) through mechanisms not yet fully elucidated. Sustained hepatic clearance of TG-rich very low density lipoproteins by the LDLr (12), statin-dependent up-regulation of the lipoprotein lipase (LPL) gene, and down-regulation of the LPL inhibitor apolipoprotein C-III (13) may all contribute to the TG-lowering effect of statins. By contrast, it is not known if statins control th...

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The lipid and non-lipid effects of statins

Cited by 224 publications

References 150 publications

Effect of atorvastatin on circulating hsCRP concentrations: A sub-study of the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study

Effect of atorvastatin on circulating hsCRP concentrations: A sub-study of the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

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