Activation of Human Peroxisome Proliferator-Activated Receptor (PPAR) Subtypes by Pioglitazone

Sakamoto, Junichi; Kimura, Hiroyuki; Moriyama, Shinji; Odaka, Hiroyuki; Momose, Yū; Sugiyama, Yasuo; Sawada, Hideki

doi:10.1006/bbrc.2000.3868

Cited by 295 publications

(198 citation statements)

References 23 publications

Supporting

Mentioning

184

Contrasting

Unclassified

Order By: Relevance

“…It is interesting to remark that at the doses used in our study, pioglitazone has no hypolipidemic effect. Because E2-KI mice respond well to PPAR␣ agonists, it appears that unlike suggested by in vitro experiments, 31,32 pioglitazone exerts very little if any PPAR␣ activity, at least under the experimental conditions tested here.…”

Section: Discussionmentioning

confidence: 46%

PPARα, but not PPARγ, Activators Decrease Macrophage-Laden Atherosclerotic Lesions in a Nondiabetic Mouse Model of Mixed Dyslipidemia

Hennuyer

Tailleux²,

Torpier³

et al. 2005

ATVB

View full text Add to dashboard Cite

Objective-Peroxisome proliferator-activated receptor (PPAR) ␣ and ␥ are nuclear receptors that may modulate atherogenesis, not only by correcting metabolic disorders predisposing to atherosclerosis but also by directly acting at the level of the vascular wall. The accumulation of lipid-laden macrophages in the arterial wall is an early pivotal event participating in the initiation and promotion of atherosclerotic lesion formation. Because PPAR␣ and ␥ modulate macrophage gene expression and cellular function, it has been suggested that their ligands may modulate atherosclerosis development via direct effects on macrophages. In this report, we investigated the effect of a PPAR␣ ligand (fenofibrate) and 2 PPAR␥ ligands (rosiglitazone and pioglitazone) on atherogenesis in a dyslipidemic nondiabetic murine model that develops essentially macrophage-laden lesions. Methods and Results-Mice were fed a Western diet supplemented or not with fenofibrate (100 mpk), rosiglitazone (10 mpk), or pioglitazone (40 mpk) for 10 weeks. Atherosclerotic lesions together with metabolic parameters were measured after treatment. Fenofibrate treatment significantly improved lipoprotein metabolism toward a less atherogenic phenotype but did not affect insulin sensitivity. Contrarily, rosiglitazone and pioglitazone improved glucose homeostasis, whereas they did not improve lipoprotein metabolism. Fenofibrate treatment significantly decreased the accumulation of lipids and macrophages in the aortic sinus. However, surprisingly, neither rosiglitazone nor pioglitazone had an effect on lesion lipid accumulation or macrophage content. Key Words: atherosclerosis Ⅲ foam cells Ⅲ peroxisome proliferator-activated receptors ␣ and ␥ Ⅲ ligands Ⅲ murine model P eroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors regulating the expression of genes that control lipid and glucose homeostasis, thus modulating the major metabolic disorders predisposing to atherosclerosis. 1 Moreover, PPARs exert additional antiinflammatory and lipid-modulating effects in the arterial wall, therefore being interesting molecular targets for the treatment of atherosclerosis. 2 PPARs are the targets of 2 classes of drugs currently used in clinical practice: fibrates (fenofibrate, clofibrate, ciprofibrate, and gemfibrozil) are PPAR␣ agonists, Conclusion-These results indicate that in a dyslipidemic See page 1763whereas thiazolidinediones (TZDs) (rosiglitazone and pioglitazone) are potent PPAR␥ activators. 3 Although the beneficial effects of fibrate treatment on coronary events and atherogenesis in humans are well-documented through epidemiological and clinical intervention studies, 4 -6 results of outcome trials with PPAR␥ agonists in humans are still awaited to answer whether treatment with TZDs translates into a therapeutic benefit in atherosclerotic cardiovascular disease. The majority of clinical studies performed to date assessed the effects of TZDs in diabetic patients and most suggested vascular protective effects of PPAR␥ ligands as ...

show abstract

Section: Discussionmentioning

confidence: 46%

PPARα, but not PPARγ, Activators Decrease Macrophage-Laden Atherosclerotic Lesions in a Nondiabetic Mouse Model of Mixed Dyslipidemia

Hennuyer

Tailleux²,

Torpier³

et al. 2005

ATVB

View full text Add to dashboard Cite

show abstract

“…In our study, pioglitazone reduced fasting triglyceride levels; however, this does not seem to be the case with rosiglitazone, which has been shown to enhance postprandial triglyceride disposal, with this effect being attributed to an improvement in the lipolysis of intact chylomicrons [46]. The reason for the differences in action of these two TZDs is not known, but may lie in the fact that pioglitazone reportedly has a greater potential than rosiglitazone to react with the PPAR-α receptor, but other differences in their pleiotropic effects or actions not involving nuclear genes cannot be ruled out [47][48][49][50]. After treatment with pioglitazone, we have also shown a significant improvement in the disposal of chylomicrons, and also in chylomicron remnant metabolism, which, coupled with the reduction in fasting VLDL and triglyceride, is responsible for a 35% improvement in postprandial triglyceride clearance.…”

Section: Discussionmentioning

confidence: 99%

The effect of sensitisation to insulin with pioglitazone on fasting and postprandial lipid metabolism, lipoprotein modification by lipases, and lipid transfer activities in type 2 diabetic patients

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis: Insulin resistance is thought to be central to the pathogenesis of diabetic dyslipidaemia. We hypothesised that improving insulin sensitivity would improve fasting and postprandial triglyceride metabolism in patients with type 2 diabetes. To this aim we studied fasting and postprandial lipaemia in type 2 diabetic patients before and after sensitisation to insulin with pioglitazone, compared with that observed in patients on an insulinproviding regime. Methods: In a double-blind placebo-controlled protocol, 22 patients with type 2 diabetes were randomly allocated to receive either pioglitazone (45 mg/day) or glibenclamide (5 mg/day), for a 20-week period. Fasting and postprandial lipid metabolism were investigated at baseline and at the end of the treatment period. A group of non-diabetic subjects was also studied. Results: Compared with glibenclamide treatment, pioglitazone treatment decreased fasting triglyceride, glucose and insulin levels and the homeostasis model assessment score of insulin resistance. Decreased fasting triglyceride after pioglitazone treatment was due to reduced VLDL triglyceride, particularly VLDL-2. Lipoprotein lipase activity was unchanged by pioglitazone treatment but hepatic lipase showed a significant decrease. Pioglitazone treatment lowered total postprandial triglyceride, as well as chylomicron-and chylomicron-remnant retinyl palmitate levels to normal. Glucose disposal improved but remained abnormal. Conclusions/interpretation: Insulin sensitisation with pioglitazone has major effects in restoring postprandial lipaemia to normal, while also correcting fasting hypertriglyceridaemia; both factors may have consequences for atherogenic risk in diabetes.

show abstract

“…First, recent study found that PPAR-␣ agonism was cardioprotective in a rat model of MI/R injury (Wayman et al, 2002). According to another report, pioglitazone has higher binding affinity to PPAR-␣ compared with rosiglitazone (Sakamoto et al, 2000). The anti-inflammatory effect of TZDs on MI/R injury may be mediated, at least partially, independently of PPAR-␥ activation (for example, by activation of the PPAR-␣ pathway).…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, Attenuates Myocardial Ischemia/Reperfusion Injury in a Rat Model

Ito

Nakano

Kinoshita

et al. 2003

Laboratory Investigation

101

View full text Add to dashboard Cite

SUMMARY:Thiazolidinediones are insulin-sensitizing drugs, ligands for peroxisome proliferator-activated receptor-␥ (PPAR-␥), which play an important role in the modulation of inflammatory responses. Myocardial ischemia/reperfusion (MI/R) injury is associated with inflammation, in which various cells, particularly monocytes and macrophages, are involved. This study examined the effects of the thiazolidinedione peroxisome proliferator-activated receptor-␥ ligand, pioglitazone, in a rat model of MI/R injury. Pioglitazone at 3 mg/kg/day or the vehicle was administered for 7 days before rats were subjected to 30 minutes of coronary ligation followed by 24 hours of reperfusion. The mRNA expression [monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1] in the ischemic region, the number of infiltrating macrophages in the ischemic region, and the myocardial infarct size were examined. The inhibitory effects of pioglitazone on activated macrophages were studied in vitro. Phorbol 12-myristate 13-acetate-induced MCP-1 production, in the absence or presence of pioglitazone, were assayed in cultured macrophages. Compared with the control group, (1) mRNA levels of MCP-1 and intercellular adhesion molecule-1 and the number of infiltrating macrophages in the ischemic region were significantly lower in the pioglitazone-treated group; and (2) myocardial infarct size was significantly smaller in the pioglitazone-treated group. Phorbol 12-myristate 13-acetate-stimulated cultured macrophages in the presence of pioglitazone produced significantly lower levels of MCP-1 than the stimulated control in the absence of pioglitazone. These observations demonstrate that pioglitazone has anti-inflammatory effects in MI/R injury that are independent of its insulin-sensitizing effect. (Lab Invest 2003, 83:1715-1721.

show abstract

Activation of Human Peroxisome Proliferator-Activated Receptor (PPAR) Subtypes by Pioglitazone

Cited by 295 publications

References 23 publications

PPARα, but not PPARγ, Activators Decrease Macrophage-Laden Atherosclerotic Lesions in a Nondiabetic Mouse Model of Mixed Dyslipidemia

PPARα, but not PPARγ, Activators Decrease Macrophage-Laden Atherosclerotic Lesions in a Nondiabetic Mouse Model of Mixed Dyslipidemia

The effect of sensitisation to insulin with pioglitazone on fasting and postprandial lipid metabolism, lipoprotein modification by lipases, and lipid transfer activities in type 2 diabetic patients

Pioglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, Attenuates Myocardial Ischemia/Reperfusion Injury in a Rat Model

Contact Info

Product

Resources

About