Differential expression and activation of a family of murine peroxisome proliferator-activated receptors.

Kliewer, Steven A.; Forman, Barry M.; Blumberg, Bruce; Ong, Estelita S.; Borgmeyer, Uwe; Mangelsdorf, David J.; Umesono, Kazuhiko; Evans, Ronald M.

doi:10.1073/pnas.91.15.7355

Cited by 1,302 publications

(955 citation statements)

References 28 publications

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“…Another PPAR family member expressed in immune cells is PPARα, which is expressed in macrophages, granulocytes, and lymphocytes Kliewer et al, 1994). The endogenous ligands for PPARα are dietary fatty acids, implying that diet can influence the immune system by activating PPARα-mediated gene expression (Varga et al, 2011).…”

Section: Ppars In T Cells and Autoimmunitymentioning

confidence: 99%

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Choi¹,

Bothwell

2012

Molecules and Cells

139

102

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Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive immunity as well as lipid metabolism. These highly conserved proteins participate in ligand-dependent or -independent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPARα, PPARβ/δ, and PPARγ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4 + T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.

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Section: Ppars In T Cells and Autoimmunitymentioning

confidence: 99%

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Choi¹,

Bothwell

2012

Molecules and Cells

139

102

View full text Add to dashboard Cite

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“…(15,16) PPARg is expressed mainly in white and brown adipose tissue and has been known to play a requisite and sufficient role in the regulation of adipocyte differentiation. (16) The transfection of fibroblastic cells with PPARg2 and its subsequent activation with ligand has been shown to be sufficient to initiate adipogenesis. (17) PPARg also acts as a molecular switch between the osteogenic and adipogenic pathways.…”

Section: Introductionmentioning

confidence: 99%

Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice

Cho

Yang

Her

et al. 2011

Journal of Bone and Mineral Research

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PPARg has critical role in the differentiation of mesenchymal stem cells into adipocytes while suppressing osteoblastic differentiation. We generated transgenic mice that overexpress PPARg specifically in osteoblasts under the control of a 2.3-kb procollagen type 1 promoter (Col.1-PPARg). Bone mineral density (BMD) of 6-to 14-week-old Col.1 À PPARg male mice was 8% to 10% lower than that of their wildtype littermates, whereas no difference was noticed in Col.1-PPARg female mice. Col.1-PPARg male mice exhibited decreased bone volume (45%), trabecular thickness (23%), and trabecular number (27%), with a reciprocal increase in trabecular spacing (51%). Dynamic histomorphometric analysis also revealed that bone-formation rate (42%) and mineral apposition rate (32%) were suppressed significantly in Col.1-PPARg male mice compared with their wild-type littermates. Interestingly, osteoclast number and surface also were decreased by 40% and 58%, respectively, in Col.1-PPARg male mice. In vitro whole-marrow culture for osteoclastogenesis also showed a significant decrease in osteoclast formation (approximately 35%) with the cells from Col.1-PPARg male mice, and OPG/RANKL ratio was reduced in stromal cells from Col.1-PPARg male mice. Although there was no significant difference in BMD in Col.1-PPARg female mice up to 30 weeks, bone loss was accelerated after ovariectomy compared with wild-type female mice (À3.9% versus À6.8% at 12 weeks after ovariectomy, p < .01), indicating that the effects of PPARg overexpression becomes more evident in an estrogen-deprived state in female mice. In conclusion, in vivo osteoblast-specific overexpression of PPARg negatively regulates bone mass in male mice and accelerates estrogen-deficiency-related bone loss in female mice. ß

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“…Peroxisome proliferator-activated receptor-b/d (PPARb/d) is a ligand-activated transcription factor of the nuclear hormone receptor superfamily (Kliewer et al, 1994). Recent studies suggest that PPAR-b may be involved in the pathogenesis of colon cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Inactivation of adenomatous polyposis coli upregulates PPAR-b expression in colon cancer (He et al, 1999), and genetic disruption of PPAR-b in colon cancer cells shows a decreased growth of xenografts (Gupta et al, 2000). Nonsteroidal anti-inflammatory drugs induce the apoptosis of colon cancer cells through direct inhibition of PPAR-b DNA-binding activity (Kliewer et al, 1994;Ouyang et al, 2006). Activation of K-ras oncogene promotes the PPAR-b expression in rat intestinal epithelia (Shao et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

et al. 2009

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The role of peroxisome proliferator-activated receptor-b/ d (PPAR-b/d) in the pathogenesis of colon cancer remains highly controversial. This study specifically silenced the PPAR-b expression in three colon cancer cell lines with different metastatic potentials. Although PPAR-b knockdown resulted in more malignant morphological changes, bigger colony sizes and lower carcinoembryonic antigen (CEA) secretion, and enhanced the cell-fibronectin adhesion, cell invasion and migration were unaffected. These effects were stronger in poorly metastatic cell lines compared with highly metastatic ones. Simultaneously, PPAR-b knockdown decreased the mRNAs encoding adipocyte differentiation-related protein and liver fatty acid binding protein, and increased the mRNA of ILK, whereas the mRNAs encoding integrin-b1 and angiopoietin-like 4 were unchanged. Using immunohistochemistry, we determined that the intensity of PPAR-b expression was stronger in rectal cancers with better differentiation than in those with poor differentiation, and was stronger in early-stage tumors than in advanced ones. Together, these findings consistently indicate that PPAR-b may facilitate differentiation and inhibit the cell-fibronectin adhesion of colon cancer, having a role as an inhibitor in the carcinogenesis and progression of colorectal cancer. Interestingly, PPAR-b seems to have a more important role in poorly metastatic cells than in highly metastatic ones.

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Differential expression and activation of a family of murine peroxisome proliferator-activated receptors.

Abstract: To gain insight into the function of peroxisome proliferator-activated receptor (PPAR) isoforms in mammals, we have cloned and characterized two PPARa-related cDNAs (deignated PPARy and -8, respectively) from mouse.

Cited by 1,302 publications

References 28 publications

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

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