Peroxisome proliferators and peroxisome proliferator activated receptors (PPARs) as regulators of lipid metabolism

Latruffe, Norbert; Vamecq, Jòseph

doi:10.1016/s0300-9084(97)81496-4

Cited by 203 publications

(123 citation statements)

References 126 publications

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“…PPARs ligands up-regulate UCP2 in adipocytes and skeletal muscles (9 -11) and unsaturated fatty acids are potent inducers of PPARs (12,13). Because in C2C12 cells the overexpression of PGC-1, a coactivator of PPAR␣ and PPAR␥, up-regulated UCP2 mRNA in the absence of ligands (14), it was suggested that PPAR␣ activation was necessary for UCP2 up-regulation in C2C12 cells.…”

Section: Ucpsmentioning

confidence: 99%

Mechanism for Peroxisome Proliferator-activated Receptor-α Activator-induced Up-regulation of UCP2 mRNA in Rodent Hepatocytes

Nakatani

Tsuboyama-Kasaoka

Takáhashi

et al. 2002

Journal of Biological Chemistry

127

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Peroxisome proliferator-activated receptor-␣ (PPAR␣) activators, fish oil feeding, or fibrate administration upregulated mitochondrial uncoupling protein (UCP2) mRNA expression in mouse liver by 5-9-fold, whereas tumor necrosis factor-␣ (TNF␣) also up-regulated UCP2 in liver. In this study, the mechanisms for PPAR␣ activators-induced up-regulation of UCP2 mRNA, related to TNF␣ and reactive oxygen species (ROS), were investigated. PPAR␣ activators-induced UCP2 up-regulation in mouse/rat liver tissues was due to their increases in hepatocytes but not in non-parenchymal cells. Addition of PPAR␣ activators, WY14,643 or fenofibrate, to cultured hepatocytes up-regulated UCP2 mRNA by 5-10-fold. PPAR␣ activators-induced up-regulation of UCP2 mRNA was not due to increased mRNA stability and required cycloheximide-sensitive short term turnover protein(s). However, expression of PPAR␣/retinoid X receptor-␣ and PGC-1 was not rate-limiting for WY14,643-induced UCP2 up-regulation. In primary hepatocytes, an exogenous oxidant, tert-butyl-hydroperoxide (TBHP), which increased ROS production, up-regulated UCP2 mRNA, whereas WY14,643 treatment did not produce detectable ROS under the condition that fibrate markedly up-regulated UCP2. In in vivo studies, PPAR␣ activators moderately up-regulated TNF␣ mRNA expression in mouse liver. An anti-oxidant pyrrolidine dithiocarbamate ammonium salt injection completely prevented their TNF␣ mRNA increases but did not prevent most of their UCP2 mRNA increases. These data indicate that PPAR␣ activators upregulate UCP2 expression in hepatocytes through unknown proteins by increased transcription, and neither ROS nor TNF␣ production are the major causes for PPAR␣ activators-induced UCP2 up-regulation.UCPs 1 (UCP1, UCP2, and UCP3) are mitochondrial transporters that are capable of dissipating the proton gradient and increasing thermogenesis while reducing the efficiency of ATP synthesis (1). In addition, there are several other hypotheses concerning the physiological roles of UCPs, regulation of fatty acid and glucose oxidation, and reduction of mitochondrial reactive oxygen species (ROS) generation (2). UCP2 was expressed in liver tissues, but hepatocytes of the adult rat liver did not express UCP2, although non-parenchymal cells especially Kupffer cells did (3). However, UCP2 in hepatocytes will be up-regulated under some metabolic conditions. Bacterial lipopolysaccharide (LPS) stimulation or lipid emulsions (linoleic or oleic acid) treatment induced UCP2 mRNA accumulation in rat hepatocytes (4, 5). Furthermore, in in vivo mice studies, fatty liver increased UCP2 expression in hepatocytes (6). We also have shown that compared with safflower oil feeding, fish oil feeding up-regulated UCP2 by 5-fold and fenofibrate administration also induced UCP2 expression by 9-fold in mouse liver tissues (7). Because n-3 fatty acids rich in fish oil and fibrate compounds are peroxisome proliferator-activated receptor-␣ (PPAR␣) activators that stimulate ␤-oxidation of fatty acids in hepatocytes, and because ther...

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Section: Ucpsmentioning

confidence: 99%

Mechanism for Peroxisome Proliferator-activated Receptor-α Activator-induced Up-regulation of UCP2 mRNA in Rodent Hepatocytes

Nakatani

Tsuboyama-Kasaoka

Takáhashi

et al. 2002

Journal of Biological Chemistry

127

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“…1). PPAR is also involved in modulating serum cholesterol levels, particularly high density lipoprotein cholesterol, in humans as well as rodents, through the regulation of target genes such as apolipoprotein (Apo) A-I, A-II and C-III (Schoonjans et al 1996, Latruffe & Vamecq 1997, Peters et al 1997.…”

Section: Ppar Mediates Responses To Ppsmentioning

confidence: 99%

Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences

Holden

Tugwood²

1999

Journal of Molecular Endocrinology

187

116

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“…PPAR␣ regulates lipid homeostasis and is a target of fibrates, which are used clinically for the treatment of hypertriglyceridemia (4,5). Fatty acids and eicosanoids are endogenous ligands for PPAR␣ (6). Ligands for PPAR␥ include the insulin-sensitizing thiazolidinediones and 15-deoxy-⌬ (12,14) PGJ 2 (7,8).…”

mentioning

confidence: 99%

WY14,643, a PPARα Ligand, Has Profound Effects on Immune Responses In Vivo

Cunard

DiCampli

Archer

et al. 2002

The Journal of Immunology

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors with diverse actions. PPARα and PPARγ are expressed in different lymphocyte subpopulations. Recently, we have observed that PPARα ligands elicit augmented IL-4 expression in cultures of mitogen-activated splenocytes. The following studies were undertaken to characterize the in vivo effects of WY14,643, a PPARα ligand. Our studies demonstrate that oral administration of WY14,643 markedly reduces splenocyte number in immunized and nonimmunized C57BL/6 mice. Mice fed WY14,643 display impaired IgG responses to myelin oligodendrocyte glycoprotein peptide 35–55 (pMOG35–55), following immunization with pMOG35–55/CFA. Following in vitro restimulation with pMOG35–55, splenocytes harvested from WY14,643-fed mice demonstrate impaired production of IFN-γ, IL-6, and TNF-α despite similar proliferative responses. We also demonstrate higher expression of PPARα in B than T cells. Finally, to obtain an understanding of the cause of splenocyte depletion with fibrate therapy, we studied the effect of WY14,643 on apoptosis of activated splenocytes. WY14,643 in vitro induces apoptosis in lymphocytes and this effect appears to occur in a PPARα-independent manner. Thus WY14,643, a fibrate, is a profound immunosuppressive agent.

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Peroxisome proliferators and peroxisome proliferator activated receptors (PPARs) as regulators of lipid metabolism

Cited by 203 publications

References 126 publications

Mechanism for Peroxisome Proliferator-activated Receptor-α Activator-induced Up-regulation of UCP2 mRNA in Rodent Hepatocytes

Mechanism for Peroxisome Proliferator-activated Receptor-α Activator-induced Up-regulation of UCP2 mRNA in Rodent Hepatocytes

Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences

WY14,643, a PPARα Ligand, Has Profound Effects on Immune Responses In Vivo

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