The mouse CCR2 gene is regulated by two promoters that are responsive to plasma cholesterol and peroxisome proliferator-activated receptor γ ligands

Chen, Yiming; Green, Simone R.; Ho, Jessica Q.; Li, Andrew; Almazan, Felizidad; Quehenberger, Oswald

doi:10.1016/j.bbrc.2005.04.110

Cited by 30 publications

(31 citation statements)

References 23 publications

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“…In addition, dietary cholesterol induced hepatic MCP1 gene expression (48), and monocyte CCR2 expression was increased in hypercholesterolemic patients compared with normocholesterolemic controls (14). Cholesterol directly stimulates the CCR2 promoter activity through its cholesterol response element (7,14), and, in this study, elevated serum cholesterol in OVX-HFHC mice increased, not only hepatocyte MCP1 expression, but also monocyte CCR2 expression in mice. Enhanced MCP1 expression in mice liver recruited CCR2-positive monocytes into the liver, and these recruited monocytes transformed into inflammatory macrophages.…”

Section: Discussionmentioning

confidence: 73%

Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet

Kamada

Kiso

Yoshida

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

137

101

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Recent studies indicate an accelerated progression of nonalcoholic steatohepatitis (NASH) in postmenopausal women. Hypercholesterolemia, an important risk factor for NASH progression, is often observed after menopause. This study examined the effects of estrogen on NASH in ovariectomized (OVX) mice fed a high-fat and high-cholesterol (HFHC) diet. To investigate the effects of estrogen deficiency, OVX mice and sham-operated (SO) mice were fed normal chow or HFHC diet for 6 wk. Next, to investigate the effects of exogenous estrogen replenishment, OVX mice fed with HFHC diet were treated with implanted hormone release pellets (containing 17β-estradiol or placebo vehicle) for 6 wk. OVX mice on the HFHC diet showed enhanced liver injury with increased liver macrophage infiltration and elevated serum cholesterol levels compared with SO-HFHC mice. Hepatocyte monocyte chemoattractant protein-1 (MCP1) protein expression in OVX-HFHC mice was also enhanced compared with SO-HFHC mice. In addition, hepatic inflammatory gene expressions, including monocytes chemokine (C-C motif) receptor 2 (CCR2), were significantly elevated in OVX-HFHC mice. Estrogen treatment improved serum cholesterol levels, liver injury, macrophage infiltration, and inflammatory gene expressions in OVX-HFHC mice. Moreover, the elevated expression of liver CCR2 and MCP1 were decreased by estrogen treatment in OVX-HFHC mice, whereas low-density lipoprotein dose dependently enhanced CCR2 expression in THP1 monocytes. Our study demonstrated that estrogen deficiency accelerated NASH progression in OVX mice fed HFHC diet and that this effect was improved by estrogen therapy. Hypercholesterolemia in postmenopausal women would be a potential risk factor for NASH progression.

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Section: Discussionmentioning

confidence: 73%

Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet

Kamada

Kiso

Yoshida

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

137

101

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“…Although the effect of synthetic PPARγ ligands on the infiltration of F4/ 80 hi CCR2 + ATM has not been studied, the reduction of this subset of ATM by ABA is in line with the well-characterized ability of PPARγ to suppress CCR2 expression. At the molecular level, the CCR2 gene contains two promoters that are both repressed by PPARγ [16], and TZDs down-regulate MCP-1-induced chemotactic response in THP-1 monocytes [34]. Moreover, in obese mice matched for adiposity, Ccr2 deficiency decreased macrophage content and WAT inflammation while ameliorating hepatic steatosis [17].…”

Section: Discussionmentioning

confidence: 96%

“…Thus, it is possible that the clinically proven efficacy of PPARγ agonists in T2D prevention and treatment [15] is also mediated via the anti-inflammatory actions of PPARγ activation in immune cells. At the molecular level, PPARγ is a direct transcriptional repressor of chemokine receptor (CCR) 2, the receptor for MCP-1 [16], which is prominently expressed in immune cells, including macrophages. Moreover, MCP-1 expression and secretion are significantly inhibited in WAT following treatment with synthetic PPARγ ligands [4,5].…”

Section: Introductionmentioning

confidence: 99%

Loss of PPARγ in immune cells impairs the ability of abscisic acid to improve insulin sensitivity by suppressing monocyte chemoattractant protein-1 expression and macrophage infiltration into white adipose tissue

Guri

Hontecillas

Ferrer

et al. 2008

The Journal of Nutritional Biochemistry

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“…This is the first report demonstrating an increase in MCP-1 expression in PPAR-␥-null macrophages. Several studies have demonstrated a repressive role for TZDs in MCP-1-and CCR2-mediated signaling pathways (9,20,45). Owing to concentration-specific PPAR-␥-independent pathways stimulated by TZDs (52), the present study sought to further characterize the PPAR-␥ dependency.…”

Section: Cytokine Analysis Of Ppar-␥-null Macrophagementioning

confidence: 98%

Expression of peroxisome proliferator-activated receptor-γ in macrophage suppresses experimentally induced colitis

Shah

Morimura

Gonzalez

2007

American Journal of Physiology-Gastrointestinal and Liver Physi

106

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Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to be a protective transcription factor in mouse models of inflammatory bowel disease (IBD). PPAR-gamma is expressed in several different cell types, and mice with a targeted disruption of the PPAR-gamma gene in intestinal epithelial cells demonstrated increased susceptibility to dextran sulfate sodium (DSS)-induced IBD. However, the highly selective PPAR-gamma ligand rosiglitazone decreased the severity of DSS-induced colitis and suppressed cytokine production in both PPAR-gamma intestinal specific null mice and wild-type littermates. Therefore the role of PPAR-gamma in different tissues and their contribution to the pathogenesis of IBD still remain unclear. Mice with a targeted disruption of PPAR-gamma in macrophages (PPAR-gamma(DeltaMphi)) and wild-type littermates (PPAR-gamma(F/F)) were administered 2.5% DSS in drinking water to induce IBD. Typical clinical symptoms were evaluated on a daily basis, and proinflammatory cytokine analysis was performed. PPAR-gamma(DeltaMphi) mice displayed an increased susceptibility to DSS-induced colitis compared with wild-type littermates, as defined by body weight loss, diarrhea, rectal bleeding score, colon length, and histology. IL-1beta, CCR2, MCP-1, and inducible nitric oxide synthase mRNA levels in colons of PPAR-gamma(DeltaMphi) mice treated with DSS were higher than in similarly treated PPAR-gamma(F/F) mice. The present study has identified a novel protective role for macrophage PPAR-gamma in the DSS-induced IBD model. The data suggest that PPAR-gamma regulates recruitment of macrophages to inflammatory foci in the colon.

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The mouse CCR2 gene is regulated by two promoters that are responsive to plasma cholesterol and peroxisome proliferator-activated receptor γ ligands

Cited by 30 publications

References 23 publications

Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet

Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet

Loss of PPARγ in immune cells impairs the ability of abscisic acid to improve insulin sensitivity by suppressing monocyte chemoattractant protein-1 expression and macrophage infiltration into white adipose tissue

Expression of peroxisome proliferator-activated receptor-γ in macrophage suppresses experimentally induced colitis

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