Activation of Peroxisome Proliferator-Activated Receptor δ Inhibits Human Macrophage Foam Cell Formation and the Inflammatory Response Induced by Very Low-Density Lipoprotein

Bojic, Lazar A.; Sawyez, Cynthia G.; Telford, Dawn E.; Edwards, Jane Y.; Hegele, Robert A.; Huff, Murray W.

doi:10.1161/atvbaha.112.255208

Cited by 47 publications

(38 citation statements)

References 48 publications

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“…Moreover, Kupffer cell-specifi c deletion of Ppard in mice resulted in increased proinfl ammatory cytokine expression and reduced anti-infl ammatory cytokine expression, which was coupled to increased liver TG accumulation and hepatic dysfunction ( 54 ). Therefore, our results are consistent with an anti-infl ammatory role for PPAR ␦ activation in the liver, similar to the effect in macrophages and in the aorta ( 28,45,47 ). The relative impact of reduced infl ammation versus correction of insulin sensitivity to the attenuation of hepatic steatosis cannot be discerned from the present experiments and requires further elucidation.…”

Section: Discussionsupporting

confidence: 80%

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PPARδ activation attenuates hepatic steatosis in Ldlr mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity

Bojic

Telford

Fullerton

et al. 2014

Journal of Lipid Research

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Hepatic steatosis, defi ned as excessive lipid accumulation in the liver, is observed in >40% of patients with type 2 diabetes ( 1, 2 ). Although a causal relationship between hepatic steatosis and insulin resistance has been diffi cult to defi ne ( 1 ), infl ammation has been implicated as a contributing factor to dysregulated hepatic insulin signaling ( 3 ). As a consequence, hyperinsulinemia-mediated lipogenesis ensues, which along with suppressed FA oxidation contributes to ectopic lipid deposition ( 4 ). Prolonged Abstract PPAR ␦ regulates systemic lipid homeostasis and infl ammation, but its role in hepatic lipid metabolism remains unclear. Here, we examine whether intervening with a selective PPAR ␦ agonist corrects hepatic steatosis induced by a high-fat, cholesterol-containing (HFHC) diet. Ldlr ؊ / ؊ mice were fed a chow or HFHC diet (42% fat, 0.2% cholesterol) for 4 weeks. For an additional 8 weeks, the HFHC group was fed HFHC or HFHC plus GW1516 (3 mg/kg/ day). GW1516-intervention significantly attenuated liver TG accumulation by induction of FA ␤ -oxidation and attenuation of FA synthesis. In primary mouse hepatocytes, GW1516 treatment stimulated AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation in WT hepatocytes, but not AMPK ␤ 1 ؊ / ؊ hepatocytes. However, FA oxidation was only partially reduced in AMPK ␤ 1 ؊ / ؊ hepatocytes, suggesting an AMPK-independent contribution to the GW1516 effect. Similarly, PPAR ␦ -mediated attenuation of FA synthesis was partially due to AMPK activation, as GW1516 reduced lipogenesis in WT hepatocytes but not AMPK ␤ 1 ؊ / ؊ hepatocytes. HFHC-fed animals were hyperinsulinemic and exhibited selective hepatic insulin resistance, which contributed to elevated fasting FA synthesis and hyperglycemia. GW1516 intervention normalized fasting hyperinsulinemia and selective hepatic insulin resistance and attenuated fasting FA synthesis and hyperglycemia. The HFHC diet polarized the liver toward a proinfl ammatory M1 state, which was reversed by GW1516 intervention. Thus, PPAR ␦ agonist treatment inhibits the progression of preestablished hepatic steatosis. -Bojic, L.

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Section: Discussionsupporting

confidence: 80%

“…6C ). A similar response of these two cytokines to GW1516 was reported in cultured macrophages ( 47 ), suggesting that a direct effect of GW1516 on the expression of Ccl3 and Il1b contributed to their decreased expression in liver following GW intervention ( Fig. 6A ).…”

Section: Gw1516 Inhibits Hepatic Infl Ammation and Induction Of Endopsupporting

confidence: 76%

PPARδ activation attenuates hepatic steatosis in Ldlr mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity

Bojic

Telford

Fullerton

et al. 2014

Journal of Lipid Research

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“…anti-inflammatory role of PPARδ in CS-related airway inflammation. It has been found that treatment with a synthetic PPARδ agonist inhibited activation of p38 MAP kinases in inflammatory circumstance, 19,28,32 which suggested a tight link between PPARδ and p38 MAPK. The MAPK family includes three members: p38, ERK and c-Jun N-terminal kinase (JNK).…”

Section: Discussionmentioning

confidence: 99%

“…18 Evidences concerning the impact of PPARδ in inflammatory process have increased in the last few years. PPARδ activation effectively inhibited very low-density lipoprotein-induced IL-1β release in THP-1 macrophages, 19 lipopolysaccharideinduced TNFα production in cardiomyocytes, 20 and TNFα-induced expression of vascular cell adhesion molecule-1 in human umbilical vein endothelial cells. 21 However, the potential roles of PPARδ in inflammatory responses of lung remain unknown.…”

mentioning

confidence: 98%

WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

Guo

Wang

et al. 2016

Laboratory Investigation

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The mechanisms of WNT/β-catenin signaling involved in airway inflammation of chronic obstructive pulmonary disease (COPD) remain unknown, although recent observations have suggested an important contribution of the pathway in pulmonary parenchymal tissue repair and airway epithelium differentiation. We investigated the role of WNT/β-catenin signaling in cigarette smoke (CS)-related airway inflammation using patient lung tissues, human bronchial epithelial cells (16HBECs), and mouse models. Reduced activity of WNT/β-catenin signaling was observed in the airway epithelium of smokers with or without COPD. The mRNA expression of WNT transcription factor TCF4 negatively correlated with the pack year. The mRNA levels of WNT receptor FZD4 negatively correlated with the mRNA levels of IL-1β. CS exposure decreased the activity of WNT/β-catenin signaling in both 16HBECs and mice. In vitro studies demonstrated the upregulation of inflammatory cytokines TNF-α and IL-1β secretion induced by CS extract (CSE) could be attenuated by β-catenin activator SB216763 and be exacerbated by β-catenin small-interfering RNA (siRNA), respectively. Furthermore, the decrease in the expression of peroxisome proliferator-activated receptor (PPARδ) induced by CSE stimulation could be rescued by SB216763. SB216763 also attenuated the upregulation of phosphorylated p38 mitogen-activated protein kinase (MAPK) stimulated by CSE. Both PPARδ agonist and p38 MAPK inhibitor could suppress the TNF-α and IL-1β release induced by CSE treatment. In addition, PPARδ activation could abolish β-catenin siRNA-mediated aggravation of phosphorylated p38 MAPK in response to CSE. Finally, SB216763 treatment significantly ameliorated peribronchial inflammatory cell infiltration, leukocyte influx, and the release of TNF-α and IL-1β in the bronchoalveolar lavage fluid of CS-exposed mice. Taken together, our findings indicate that the reduced activity of WNT/β-catenin signaling induced by CS may promote inflammatory cytokine production in airway epithelium and have an essential role in airway inflammation in COPD by PPARδ/p38 MAPK pathway.

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“…signaling [32]. The anti-inflammatory effects of PPARD agonists in macrophages have been shown by several groups.…”

Section: Macrophagesmentioning

confidence: 97%

Peroxisome proliferator-activated receptor delta and cardiovascular disease

Skogsberg

2013

Atherosclerosis

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Activation of Peroxisome Proliferator-Activated Receptor δ Inhibits Human Macrophage Foam Cell Formation and the Inflammatory Response Induced by Very Low-Density Lipoprotein

Cited by 47 publications

References 48 publications

PPARδ activation attenuates hepatic steatosis in Ldlr mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity

PPARδ activation attenuates hepatic steatosis in Ldlr mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity

WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

Peroxisome proliferator-activated receptor delta and cardiovascular disease

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