PPAR-gamma: Difference between revisions

== Introduction ==  

Peroxisome proliferator-activated receptor gamma (<scene name='PPAR-gamma/Ppar_gamma/3'>PPAR</scene>γ) is a protein in the nuclear receptors subfamily.  It is one of three isotypes (-α, -β/ δ, and -γ) [1] of [[PPAR]] receptors and has two protein isoforms governed by splice variations, which result in differences in the length of the amino (N)-terminal region (PPARγ1 and PPARγ2) [2].  PPARγ is involved in transcriptional regulation of glucose and lipid homeostasis [1], and helps regulate adipocyte differentiation [3].  It has a <scene name='PPAR-gamma/Binding_pocket/1' target='1'>large binding pocket</scene>, which allows it to interact with a wide array of ligands.  <scene name='PPAR-gamma/Interacting_residues/3'>Ligand binding</scene> typically triggers a conformational change of PPARγ, notably in the activation function-2 <scene name='PPAR-gamma/Af-2_domain/2'>(AF-2) domain</scene>, which aids in the recruitment of co-regulatory factors to regulate gene transcription.  PPARγ can form a <scene name='PPAR-gamma/Ppar_rxr/3'>heterodimer</scene> with retinoic X receptor alpha (RXRα), a process necessary for most PPARγ-DNA interactions [4].  PPARγ is a molecular target for antidiabetic drugs such as thiazolidinediones (TZDs), which makes the protein a target for Type II Diabetes (T2D) drug research.  Due to its involvement in metabolic and inflammatory processes, PPARγ also holds potential for treatments of many metabolic and chronic-inflammatory diseases, such as metabolic syndrome and inflammatory bowel disease, respectively.  Errors in PPARγ-related regulation have also been implicated in atherosclerosis and various cancers, like colorectal, breast, and prostate cancers.

== Overall Structure and Ligand Binding ==

PPARγ is composed of the ligand-independent activation domain (AF-1 region and A/B-domain), a DNA-binding domain (DBD) (C-domain), a hinge region (D-domain), and a ligand-dependent ligand-binding domain (LBD) (E/F-domain and AF-2 region) [5].  The two PPARγ isoforms, PPARγ1 and PPARγ2, differ by only 30 amino acids at the N-terminal end.  These added amino acids on PPARγ2 result in increased potency and adipose-selectivity, which makes this protein a key player of adipocyte differentiation [3].   

The <scene name='PPAR-gamma/Lbd/2' target='2'>ligand binding domain</scene> is composed of 13 α helices and 4 short β strands [1].  It has a T-shaped binding pocket with a volume of ~1440 Å3 [1, 6], which is larger than that of most nuclear receptors [7], allowing for interactions with a variety of ligands [8].  The PPARγ LBD is folded into a helical sandwich to provide a binding site for ligands.  It is located at the C-terminal end of PPARγ and is composed of about 250 amino acids [5].  Activation by full agonists occurs through hydrogen bond interactions between the S289, H323, Y473, and H449 residues of the PPARγ-LBD [7] and polar functional groups on the ligand which are typically carbonyl or carboxyl oxygen atoms.  Agonist binding results in a conformational change of the LBD AF-2 region, which is necessary for coactivator recruitment.  This change can either be dramatic or subtle [1], which leads to stabilization of a charge clamp between helices H3 and H12 [9] to aid in associations with the LXXLL (L, leucine; X, any amino acid) motif of the coactivator [1, 10].  Ligand binding of PPARγ is regulated by communication between the N-terminal A/B domain, which is adjacent to the DBD, and the carboxyl-terminal LBD [11].   

== Ligand Activity ==

PPARγ is found in high levels in colonic epithelial cells.  The role of PPARγ in these cells may be related to regulation of immune response and colon inflammation [12].  The onset of Inflammatory Bowel Disease is thought to be caused by inflammatory cytokines present in the colon [12].  In patients with ulcerative colitis, colonic epithelial cells displayed impaired expression of PPARγ, an important mediator of aminosalicylate activities in Inflammatory Bowel Diseases [13].  TZD ligands could be implemented to reduce colonic inflammation [12].  Agonists have also been used in the treatment of colitis and psoriasis by inhibiting the inflammatory response of the epithelium and reducing cytokine production [8].  PPARγ inhibits activity of nuclear factor NFκB, which is higher in active ulcerative colitis patients [15].   

PPARγ could also be implemented in the treatment of other chronic inflammation-related diseases. Immunomodulatory effects have been found with PPARγ agonists [16].  Rosiglitazone alongside adiponectin reduces renal disease, atherosclerosis, and production of autoantibodies, all of which are characteristic of the inflammatory autoimmune disease Systemic Lupus Erythematosus (SLE) [16].  PPARγ ligands hold potential as cancer treatments [11] due to their ability to inhibit angiogenesis, the process required for the growth and metastasis of solid tumors [8]. PPARγ activators have pro-differentiation and anti-proliferation effects [3].  TZDs have also been shown to inhibit proliferation of human breast, prostate, and colon cancer cells [8].   

==3D structures of PPAR==