I. Introduction II. Molecular Aspects A. PPAR isotypes: identity, genomic organization and chromosomal localization B. DNA binding properties C. PPAR ligand-binding properties D. Alternative pathways for PPAR activation E. PPAR-mediated transactivation properties III. Physiological Aspects A. Differential expression of PPAR mRNAs B. PPAR target genes and functions in fatty acid metabolism C. PPARs and control of inflammatory responses D. PPARs and atherosclerosis E. PPARs and the development of the fetal epidermal permeability barrier F. PPARs, carcinogenesis, and control of the cell cycle IV. Conclusions

Peroxisome proliferator-activated receptors: nuclear control of metabolism.

▪ Abstract The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARγ, PPARα, and PPARδ, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we presen...

The Mechanisms of Action of PPARs

https://www.cell.com/molecular-cell/pdf/S1097-2765(00)80211-7.pdf

PPARγ Is Required for the Differentiation of Adipose Tissue In Vivo and In Vitro

The PPARs: from orphan receptors to drug discovery.

I. Introduction II. Nuclear Receptors: General Concepts A. Anatomy of nuclear receptors B. Mechanisms of action III. Orphan Nuclear Receptors A. Definition B. Nomenclature C. Structural and functional diversity IV. Novel Hormone Response Systems: RXR and Its Heterodimeric Partners A. RXR: rexinoids B. PPAR: multiple ligands, multiple functions C. PXR: pregnanes, xenobiotic compounds, and benzoate derivatives D. CAR (constitutive androstane receptor): androstanes and phenobarbital E. LXR: control of cholesterol metabolism by oxysterols F. FXR: bile acids receptor V. Orphans in Search of a Home A. HNF4: diabetes and possible regulation by acyl-coenzyme A (CoA) thioesters B. FTZ-F1: steroidogenesis and sexual development C. Rev-Erb: singular members of the superfamily D. ROR: neuron development and T cell selection E. TR2: the testis receptors F. TLX: forebrain development G. COUP-TF: neurogenesis, angiogenesis, and heart development H. ERR: placenta development and control of lipid metabolism I. NGFI-B: hyp...

/pdf/orphan-nuclear-receptors-from-gene-to-function-28jgs4505b.pdf

Orphan nuclear receptors: from gene to function.

Induction of differentiation and apoptosis in cancer cells through ligands of nuclear hormone receptors (NHRs) is a novel and promising approach to cancer therapy. All-trans-retinoic acid (ATRA), an RA receptor-specific NHR ligand, is now used for selective cancers. The NHR, peroxisome proliferator-activated receptor γ (PPARγ) is expressed in breast cancer cells. Activation of PPARγ through a synthetic ligand, troglitazone (TGZ), and other PPARγ-activators cause inhibition of proliferation and lipid accumulation in cultured breast cancer cells. TGZ (10−5 M, 4 days) reversibly inhibits clonal growth of MCF7 breast cancer cells and the combination of TGZ (10−5 M) and ATRA (10−6 M, 4 days) synergistically and irreversibly inhibits growth and induces apoptosis of MCF7 cells, associated with a dramatic decrease of their bcl-2 protein levels. Similar effects are noted with in vitro cultured breast cancer tissues from patients, but not with normal breast epithelial cells. The observed apoptosis mediated by TGZ and ATRA may be related to the striking down-regulation of bcl-2, because forced over-expression of bcl-2 in MCF7 cells cultured with TGZ and ATRA blocks their cell death. TGZ significantly inhibits MCF7 tumor growth in triple immunodeficient mice. Combined administration of TGZ and ATRA causes prominent apoptosis and fibrosis of these tumors without toxic effects on the mice. Taken together, this combination may provide a novel, nontoxic and selective therapy for human breast cancers.

https://www.pnas.org/content/pnas/95/15/8806.full.pdf

Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice.

K Koshizuka

Papers

Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice.