Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?

Peroxisomal proliferators, such as ciprofibrate, are used extensively as effective hypolipidemic drugs. The effects of these compounds on lipid metabolism require ligand binding activation of the peroxisome proliferatoractivated receptor (PPAR) a subtype of nuclear receptors and involve transcriptional activation of the metabolic pathways involved in lipid oxidative metabolism, transport, and disposition. v-Hydroxylated-eicosatrienoic acids (HEETs), products of the sequential metabolism of arachidonic acid (AA) by the cytochrome P450 CYP2C epoxygenase and CYP4A v-hydroxylase gene subfamilies, have been identified as potent and high-affinity ligands of PPARa in vitro and as PPARa activators in transient transfection assays. Using isolated rat hepatocytes in culture, we demonstrate that specific inhibition of either the CYP2C epoxygenase or the CYP4A v-hydroxylase abrogates ciprofibrate-induced peroxisomal proliferation, whereas inhibition of other eicosanoid-synthesizing pathways had no effect. Conversely, overexpression of the rat liver CYP2C11 epoxygenase leads to spontaneous peroxisomal proliferation, an effect that is reversed by a CYP inhibitor. Based on these results, we propose that HEETs may serve as endogenous PPARa ligands and that the P450 AA monooxygenases participate in ciprofibrate-induced peroxisomal proliferation and the activation of PPARa downstream targets.-Gatica, A

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“…P450 monooxygenases mediate peroxisomal proliferationperoxisome proliferation-unresponsive species, such as humans (55,56).…”

Section: Discussionmentioning

confidence: 99%

P450 CYP2C epoxygenase and CYP4A ω-hydroxylase mediate ciprofibrate-induced PPARα-dependent peroxisomal proliferation

Gatica

Aguilera

Contador

et al. 2007

Journal of Lipid Research

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“…However, nonrodent species were shown to be refractory to the induction of peroxisome proliferation (33). In fact, the fibrate class of PPAR-␣ agonists has been safely used in humans to treat hypertriglyceridemia, and no hepatic carcinogenesis has been reported (34). Although the effect of PPAR-␣ activation on insulin sensitivity is inconclusive in humans, some recent clinical studies have shown improved insulin sensitivity by fibrates (35,36).…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor (PPAR)-α Activation Prevents Diabetes in OLETF Rats

et al. 2003

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Lipid accumulation in nonadipose tissues is closely related to the development of type 2 diabetes in obese subjects. We examined the potential preventive effect of peroxisome proliferator-activated receptor (PPAR)-␣ and PPAR-␥ stimulation on the development of diabetes in obese diabetes-prone OLETF rats. I ncreasing evidence suggests that lipid accumulation in nonadipose tissues, such as skeletal muscle and pancreatic islet, is causally related to the development of type 2 diabetes in obese individuals (1,2). Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear transcription factors that regulate lipid metabolism (3). Thiazolidinedione (TZD), a high-affinity ligand for PPAR-␥, is now widely used as an insulin-sensitizing drug (4) and has been shown to reduce fat accumulation in skeletal muscle (5). TZD has also been suggested to reduce fat accumulation in other nonadipose tissues such as islets and heart (6). However, these favorable effects of TZD on nonadipose tissues may not arise directly from PPAR-␥ activation in these tissues. PPAR-␥ is highly expressed in adipose tissue, but its expression is low in nonadipose tissues such as skeletal muscle or pancreatic ␤-cells (7). Therefore, it has been suggested that TZD improves muscle insulin action and prevents apoptosis of pancreatic ␤-cells by sequestering lipids in adipose tissue (8) or by increasing production of adiponectin (9), an adipocytokine that has been shown to increase insulin sensitivity (10).The role of PPAR-␣ in the regulation of intracellular lipid homeostasis in nonadipose tissues may be more straightforward. Normally, it is expressed in nonadipose tissues at relatively high levels compared with PPAR-␥ (11). PPAR-␣ is a transcription factor that has been shown to upregulate fatty acid oxidative enzymes mainly in the liver (12), but recent studies have indicated that it also increases fatty acid oxidation in skeletal muscle (13). It was also reported that PPAR-␣ stimulators increase insulin sensitivity and reduce adiposity (14) and lipid accumulation in skeletal muscle (5). The expression of PPAR-␣ and enzymes of fatty acid oxidation is markedly reduced in the fat-laden dysfunctional islets of obese prediabetic Zucker diabetic fatty (fa/fa) rats (15). It is unknown, however, whether PPAR-␣ stimulators can prevent ␤-cell destruction and diabetes in diabetes-prone animals. The present study was therefore undertaken to examine the potential preventive effects of PPAR-␣ stimulation on the development of diabetes in Otsuka Long Evans Tokushima Fatty (OLETF) rats, an animal model of obesity and diabetes. RESEARCH DESIGN AND METHODS Animals.Male OLETF rats and their lean nondiabetic counterparts, LongEvans Tokushima Otsuka (LETO) rats, were supplied at 4 weeks of age by the Otsuka Pharmaceutical Company (Tokushima, Japan). The rats were maintained at an ambient temperature (22 Ϯ 1°C) with 12:12-h light-dark cycles and free access to water and rat food. All procedures were approved by the Institutional Animal Care ...

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“…Such peroxisome proliferation is ultimately associated with an increased incident of hepatocarcinoma (Lake, 1995). However, it has been subsequently found that such PPAR agonists do not induce peroxisome proliferation (or cancer) in a number of species including guinea pigs, primates and humans (Cattley et al, 1998;Choudhury et al, 2000). In fact, fibrates, known PPARa ligands, have been commonly used in the treatment of elevated plasma lipids for many years (Watts and Dimmitt, 1999).…”

Section: Nuclear Receptorsmentioning

confidence: 99%

Regulation of gene transcription by fatty acids

Salter

Tarling

2007

Animal

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Dietary fat is well recognised as an important macronutrient that has major effects on growth, development and health of all animals including humans. The amount and type of fat in the diet impacts on many aspects of metabolism including lipoprotein pathways, lipid synthesis and oxidation, adipocyte differentiation and cholesterol metabolism. It has become increasingly apparent that many of these effects may be due to direct modulation of expression of key genes through the interaction of fatty acids with certain transcription factors. Peroxisome proliferator-activated receptors (PPARs), the liver X receptors (LXRs), hepatic nuclear factor 4 (HNF-4) and sterol regulatory binding proteins (SREBPs) represent four such factors. This review focuses on emerging evidence that the activity of these transcription factors are regulated by fatty acids and the interactions between them may be responsible for many of the effects of fatty acids on metabolism and the development of chronic disease.

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Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?

Cited by 214 publications

References 68 publications

P450 CYP2C epoxygenase and CYP4A ω-hydroxylase mediate ciprofibrate-induced PPARα-dependent peroxisomal proliferation

P450 CYP2C epoxygenase and CYP4A ω-hydroxylase mediate ciprofibrate-induced PPARα-dependent peroxisomal proliferation

Peroxisome Proliferator-Activated Receptor (PPAR)-α Activation Prevents Diabetes in OLETF Rats

Regulation of gene transcription by fatty acids

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