PPARα deficiency does not modify age dependency but prevents high fat diet increase in plasma PAI-1 as well as insulin resistance

Mavri, Alenka; Bastelica, Delphine; Staels, Bart; Ayachi, Soulaf El; Juhan‐Vague, I.; Alessi, Marie‐Christine

doi:10.1055/s-0037-1614204

Cited by 4 publications

(1 citation statement)

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“…Our data are in accordance with a report showing decreased PAI-1 expression in adipose tissue of hypercholesterolaemic rabbits treated with fenofibrate, a PPARα activating drug (45). In contrast, Mavri et al described markedly reduced PAI-1 plasma levels in PPARα-deficient mice (53). Similarly Guerre-Millo et al revealed the unexpected finding that PPARα-deficient mice are protected from insulin resistance and obesity (54).…”

Section: Discussionsupporting

confidence: 93%

Inhibition by fibrates of plasminogen activator inhibitor type-1 expression in human adipocytes and preadipocytes

Zirlik

Schwartz²,

Leugers³

et al. 2009

Thromb Haemost

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SummaryPlasminogen activator inhibitor type-1 (PAI-1), an established marker and mediator of cardiovascular risk, is produced extensively in adipose tissue. Fibrates are hypolipidemic peroxisome proliferator activated receptor-alpha (PPARα) agonists. Recent laboratory and clinical observations indicate that they are also anti-atherosclerotic. Mechanisms responsible, however, remain to be fully understood. The present study was designed to elucidate modulation of PAI-1 expression in adipose cells by fibrates as a potential mechanism. Expression of PPARα was verified by PCR, immunohistochemistry, and Western blotting. In cultured preadipocytes and adipocytes gemfibrozil and fenofibrate significantly reduced PAI-1 protein expression by up to 55 ± 5% and 34 ± 4% under basal conditions and up to 56 ± 6% and 31 ± 6% under conditions of stimulation of the cells with 40 pM trans-Keywords forming growth factor (TGF)β, respectively. Quantification of mRNA showed that the gemfibrozil-induced effect was at least in part regulated at the transcriptional level. Incubations with non-fibrate PPARα agonists showed similar reductions in PAI-1 expression. The decrease in PAI-1 expression induced by gemfibrozil was inhibited by MK886, a PPARα inhibitor. Furthermore, preadipocytes isolated from PPARα-deficient mice produced significantly more PAI-1 than those from wild-type mice upon stimulation with TGFβ. Finally, fenofibrate reduced PAI-1 expression both in plasma and adipose tissue of hyperlipidemic mice. Our data support the view that PPARα activation down-regulates PAI-expression in adipose cells that may contribute in part to the reduction in cardiovascular mortality seen with fibrates in clinical trials.

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Section: Discussionsupporting

confidence: 93%

Inhibition by fibrates of plasminogen activator inhibitor type-1 expression in human adipocytes and preadipocytes

Zirlik

Schwartz²,

Leugers³

et al. 2009

Thromb Haemost

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Absence of Peroxisome Proliferator-Activated Receptor-α Abolishes Hypertension and Attenuates Atherosclerosis in the Tsukuba Hypertensive Mouse

Tordjman

Semenkovich²,

Coleman³

et al. 2007

Hypertension

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Abstract-Peroxisome proliferator-activated receptor-␣ is widely distributed in the vasculature where it is believed to exert pleiotropic antiatherogenic effects. Its role in the regulation of blood pressure is still unresolved; however, some evidence suggests that it may affect the renin-angiotensin system. We investigated its role in angiotensin II-induced hypertension in the Tsukuba hypertensive mouse (THM). This is a model of hypertension and atherosclerosis because of high angiotensin II and aldosterone levels as a result of the transgenic expression of the entire human renin-angiotensin system. Making the THM animals deficient in Peroxisome proliferator-activated receptor-␣ (THM/ PPARKO) totally abolished hypertension and myocardial hypertrophy. This was accompanied by a reduction in plasma human active renin in THM/PPARKO mice compared with THM animals from 3525Ϯ128 mU/L to 1910Ϯ750 mU/L (PϽ0.05) and by a normalization of serum aldosterone (1.6Ϯ0.29 nmol/L versus 3.4Ϯ0.69 nmol/L; Pϭ0.003). In the THM/PPARKO mice, the extent of atherosclerosis at the aortic sinus after a 12-week period on an atherogenic diet was decreased by Ͼ80%. In addition, the spontaneous formation of foam cells from peritoneal macrophages, a blood pressure-independent event, was reduced by 92% in the THM/PPARKO mice, suggesting protection from the usual oxidative stress in these animals, possibly because of lower prevailing angiotensin II levels. Finally, chronic fenofibrate treatment further elevated blood pressure in THM animals but not in THM/PPARKO animals. Taken together, these data indicate that peroxisome proliferator-activated receptor-␣ may regulate the renin-angiotensin system. They raise the possibility that its activation may aggravate hypertension and hasten atherosclerosis in the context of an activated renin-angiotensin system. (Hypertension. 2007;50:945-951.)Key Words: PPAR␣ Ⅲ renin Ⅲ angiotensin Ⅲ hypertension Ⅲ atherosclerosis Ⅲ transgenic mice F irst identified and cloned from the liver as the nuclear receptor that mediates peroxisomal proliferation, proliferator-activated receptor (PPAR)-␣ has been found to be widely expressed in all of the cellular components of the vascular wall, where it is shown to exert pleiotropic antiatherogenic effects. Thus, in addition to its lipid-lowering effect, which mostly takes place in the liver, PPAR␣ is believed to impart direct protection in the vessel wall by intervening at essentially every level of the atherogenic process: inflammation, monocyte recruitment and adhesion, cholesterol transport, plaque formation, and thrombosis, mostly through downregulation of nuclear factor B and activator protein-1 (AP-1). [1][2][3] In contrast to the plethora of data regarding the atherogenic process, the role of PPAR␣ in the regulation of vascular tone and blood pressure is still unclear. Several studies conducted in different rat models of hypertension yielded inconsistent results. 4,5 In a previous study, we reported that the atherosclerosisprone apolipoprotein E (apoE)-null mice were pro...

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Peroxisome Proliferator-Activated Receptor-α-Null Mice Have Increased White Adipose Tissue Glucose Utilization, GLUT4, and Fat Mass: Role in Liver and Brain

et al. 2006

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Activation of the peroxisome proliferator-activated receptor (PPAR)-alpha increases lipid catabolism and lowers the concentration of circulating lipid, but its role in the control of glucose metabolism is not as clearly established. Here we compared PPARalpha knockout mice with wild type and confirmed that the former developed hypoglycemia during fasting. This was associated with only a slight increase in insulin sensitivity but a dramatic increase in whole-body and adipose tissue glucose use rates in the fasting state. The white sc and visceral fat depots were larger due to an increase in the size and number of adipocytes, and their level of GLUT4 expression was higher and no longer regulated by the fed-to-fast transition. To evaluate whether these adipocyte deregulations were secondary to the absence of PPARalpha from liver, we reexpresssed this transcription factor in the liver of knockout mice using recombinant adenoviruses. Whereas more than 90% of the hepatocytes were infected and PPARalpha expression was restored to normal levels, the whole-body glucose use rate remained elevated. Next, to evaluate whether brain PPARalpha could affect glucose homeostasis, we activated brain PPARalpha in wild-type mice by infusing WY14643 into the lateral ventricle and showed that whole-body glucose use was reduced. Hence, our data show that PPARalpha is involved in the regulation of glucose homeostasis, insulin sensitivity, fat accumulation, and adipose tissue glucose use by a mechanism that does not require PPARalpha expression in the liver. By contrast, activation of PPARalpha in the brain stimulates peripheral glucose use. This suggests that the alteration in adipocyte glucose metabolism in the knockout mice may result from the absence of PPARalpha in the brain.

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PPARα deficiency does not modify age dependency but prevents high fat diet increase in plasma PAI-1 as well as insulin resistance

Cited by 4 publications

References 0 publications

Inhibition by fibrates of plasminogen activator inhibitor type-1 expression in human adipocytes and preadipocytes

Inhibition by fibrates of plasminogen activator inhibitor type-1 expression in human adipocytes and preadipocytes

Absence of Peroxisome Proliferator-Activated Receptor-α Abolishes Hypertension and Attenuates Atherosclerosis in the Tsukuba Hypertensive Mouse

Peroxisome Proliferator-Activated Receptor-α-Null Mice Have Increased White Adipose Tissue Glucose Utilization, GLUT4, and Fat Mass: Role in Liver and Brain

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