PPARδ is a very low-density lipoprotein sensor in macrophages

Chawla, Ajay; Lee, Chih‐Hao; Barak, Yaacov; He, Weimin; Rosenfeld, John M.; Liao, Daiqing; Han, Jungyeob; Kang, Heonjoong; Evans, Ronald M.

doi:10.1073/pnas.0337331100

Cited by 278 publications

(221 citation statements)

References 46 publications

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“…Similar compensatory changes in the expression of genes that increase hepatic cholesterol have been observed in mice overproducing liver derived HDL (54). Recently, it was reported that VLDL-TG hydrolyzed by LPL strongly activates the expression of a series of "lipid storage" genes in macrophages via PPAR␤, indicating that PPAR␤ is a VLDL sensor in these cells (55). It is conceivable that, in the absence of PPAR␤, extrahepatic cells such as macrophages, are unable to properly detect or uptake lipids found in VLDL and the increased hepatic production of VLDL represents a compensatory response.…”

Section: Ppar␤-null Mice On An Hf Diet Exhibit Lowered Body Weight Anmentioning

confidence: 60%

Peroxisome Proliferator-activated Receptor β/δ Regulates Very Low Density Lipoprotein Production and Catabolism in Mice on a Western Diet

Akiyama

Lambert

Nicol

et al. 2004

Journal of Biological Chemistry

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The results of recent studies using selective agonists for peroxisome proliferator-activated receptor ␤ (PPAR␤) suggest that this receptor may have a role in regulating levels of serum lipids in animal models of obesity and insulin resistance. To further examine this possibility, serum lipid profiles of mice lacking a functional PPAR␤ receptor were determined. PPAR␤-null mice maintained on either normal chow or a 10-week high fat (HF) diet, a condition that has been shown to induce insulin resistance and obesity in mice, have elevated levels of serum triglycerides primarily associated with very low density lipoprotein (VLDL) with no difference in either total cholesterol or phospholipids. Consistent with this finding, PPAR␤-null mice on a HF-diet were shown to have an increased rate of hepatic VLDL production as well as lowered lipoprotein lipase activity in serum compared with wild-type controls. The latter parallels an increase in the hepatic expression of the genes encoding angiopoietin-like proteins 3 and 4 in PPAR␤-null mice on a HF diet, both proteins of which have recently been shown to inhibit lipoprotein lipase (LPL) activity in vivo. Consistent with elevated VLDL production, a marked increase in plasma VLDL apoB48, -E, -AI, and -AII, as well as a sharp depletion of the hepatic lipid stores was also found in PPAR␤-null mice. In addition, PPAR␤-null mice on a HF diet were shown to have increased adiposity, despite lower total body weight. Together, these results indicate a clear role for PPAR␤ in regulating levels of serum triglycerides in mice on a high fat Western diet by modulating both VLDL production and LPL-mediated catabolism of VLDL-triglycerides and also suggest a potential therapeutic role for PPAR␤ in the improvement of serum lipids in the setting of metabolic syndrome.The peroxisome proliferator-activated receptors (PPARs) 1 are members of the nuclear hormone receptor superfamily.

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Section: Ppar␤-null Mice On An Hf Diet Exhibit Lowered Body Weight Anmentioning

confidence: 60%

Peroxisome Proliferator-activated Receptor β/δ Regulates Very Low Density Lipoprotein Production and Catabolism in Mice on a Western Diet

Akiyama

Lambert

Nicol

et al. 2004

Journal of Biological Chemistry

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“…Prostaglandin A1 (PGA1), PGD2 and PGD1 can activate PPARβ/δ in reporter assays [27]. Similar to PPARα and γ, incubation of triglyceride rich lipoproteins with LPL results in the production of PPARβ ligands [28,29]. We have shown here that several molecules present in oxVLDL including 15-HETE, 13(S)-HODE and 4-HNE are agonists of PPARβ/δ ( Fig.…”

Section: Discussionmentioning

confidence: 78%

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Coleman

Prabhu

Thompson

et al. 2007

Free Radical Biology and Medicine

104

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Liver insufficiency and damage is a major cause of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPARβ/δ −/− mouse is more susceptible to chemically-induced hepatotoxicity than its wildtype counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPARβ/δ confers protection to hepatocytes. We hypothesized that PPARβ/ δ plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadeca-dienoic acid (13(S)-HODE) and 4-HNE are PPARβ/δ ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARβ/δ subtype while 4-hyroxy-hexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPARβ/δ activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPARβ/δ-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPARβ/δ activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage.

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“…27) VLDL, which is also a triglyceride-rich lipoprotein particle, functions as a transcriptional regulator via activation of the PPARδ in macrophages. 28) PPARδ is also one of the target genes of Wnt signaling, which is relevant to carcinogenesis. 29) Therefore, high levels of serum triglyceride and VLDL may enhance the growth of intestinal polyps in Apc-deficient mice through activation of PPARδ in their intestines.…”

Section: Discussionmentioning

confidence: 99%

Dose‐dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPARγ ligand

Niho¹,

Takahashi²,

Shoji³

et al. 2003

Cancer Science

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In our previous study, a peroxisome proliferator-activated receptor γ γ γ γ (PPARγ γ γ γ) agonist, pioglitazone, suppressed both hyperlipidemia and intestinal polyp formation in Apc 1309 mice at doses of 100 and 200 ppm in the diet. In contrast, it has been reported that doses of 1500 or 2000 ppm of another PPARγ γ γ γ agonist, troglitazone, enhanced colon polyp development in Min mice. In the present study, we therefore investigated the effects of a wide range of pioglitazone doses on both hyperlipidemia and intestinal polyp formation in Min mice. Serum triglycerides and very low density lipoprotein (VLDL) cholesterol in the basal diet group were elevated to levels 13-15 times higher than those in the wild-type counterparts at 20 weeks of age. They were reduced dose-dependently by treatment with 100, 200, 400 and 1600 ppm pioglitazone from 6-20 weeks of age with suppression to almost the wild-type level at the highest dose. Moreover, up-regulation of the liver mRNA levels for lipoprotein lipase (LPL) was evident in the pioglitazone-treated animals. Dose-dependent reduction of intestinal polyps was observed in Min mice given 100-1600 ppm for 14 weeks, total numbers being decreased to 63-9% of the control value. A suppressive effect of pioglitazone on colon polyp formation was also found. The PPARγ γ γ γ agonist, pioglitazone, may thus be a promising candidate chemopreventive agent for colon cancer. onsumption of a high fat diet is epidemiologically related to the risk of colon cancer.

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PPARδ is a very low-density lipoprotein sensor in macrophages

Cited by 278 publications

References 46 publications

Peroxisome Proliferator-activated Receptor β/δ Regulates Very Low Density Lipoprotein Production and Catabolism in Mice on a Western Diet

Peroxisome Proliferator-activated Receptor β/δ Regulates Very Low Density Lipoprotein Production and Catabolism in Mice on a Western Diet

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Dose‐dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPARγ ligand

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