Receptor

About: Receptor is a research topic. Over the lifetime, 159318 publications have been published within this topic receiving 8299881 citations.

Growth, Adipose, Brain, and Skin Alterations Resulting from Targeted Disruption of the Mouse Peroxisome Proliferator-Activated Receptor β(δ)

Abstract: In the past 10 years, specific roles for peroxisome proliferator-activated receptor α (PPARα) and PPARγ have emerged while information defining PPARβ-dependent processes is lacking. PPARs are members of the nuclear receptor superfamily (34). The three PPARs exhibit unique tissue distribution, are encoded by separate genes in all species examined to date, and are designated by the subtypes α, β (δ, NUC1), and γ (14, 18, 34, 47, 48). Acting as regulatory transcription factors, the PPARs heterodimerize with retinoid X receptors and modulate gene expression in target genes containing peroxisome proliferator-responsive elements (PPREs) in response to ligand activation. The three PPARs have related but distinct activities. Activation of PPARα can occur as a result of cold shock (19), food restriction (26), dietary fatty acids (44), and treatment with the hypolipidemic fibrate class of drugs (31). Peroxisomal and mitochondrial β-oxidizing enzymes, microsomal ω-oxidizing enzymes, hepatic fatty acid binding protein, carnitine palmitoyltransferases, and a number of apolipoproteins are all regulated by PPARα ligands/activators (3, 26, 31, 38, 41, 44). These data, obtained in part from the PPARα-null mouse, provide strong in vivo evidence that PPARα regulates lipid metabolism by regulating gene expression of numerous proteins which are clinically relevant for a number of diseases including diabetes, obesity, and atherosclerosis. Another PPAR isoform, PPARγ, is required for adipocyte differentiation and regulation of adipocyte-specific genes such as the gene for adipocyte fatty acid binding protein aP2 (47). Similar to PPARα, PPARγ is activated by specific ligands, most notably the thiazolidinedione drugs used for type 2 diabetes therapy (32). The phenotype of a PPARγ-null mouse line is embryo lethal due in part to disrupted placental function (4). Tetraploid rescue experiments to bypass the placental defect confirmed an in vivo role for the receptor in adipogenesis (4). Analysis of heterozygotes and chimeras also established a role for PPARγ in adipocyte function and glucose homeostasis (29, 45). Thus, it is clear from null mouse studies that there are distinct metabolic roles for PPARα and PPARγ. The function of PPARβ has remained elusive. While PPARβ is ubiquitously expressed, some tissues express relatively higher levels of the mRNA including the brain, adipose tissue, and skin (2, 8). Expression of PPARβ is considerably higher in the developing neural tube and the epidermis during rat development (9). No target genes that are controlled only by PPARβ have been identified, but activators for PPARβ including fatty acids (27), bezafibrate (28), and a furan-conjugated linoleic acid metabolite (39) are reported to activate reporter gene constructs containing PPREs through PPARβ. Despite the lack of a specific PPARβ ligand to induce activation, there are several reports suggesting roles for PPARβ in adipocyte differentiation (5), brain function (51), epidermal differentiation (37), uterine implantation (33), and colon cancer (20). In large part, these studies are correlative associations; definitive proof for PPARβ function requires the use of a null mouse model. In the present study, a PPARβ-null mouse was generated and characterized to identify physiological functions dependent on PPARβ.

Interleukin-18 and IL-18 binding protein.

Abstract: Interleukin-18 (IL-18) is a member of the IL-1 family of cytokines. Similar to IL-1β, IL-18 is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine but unlike IL-1β, the IL-18 precursor is constitutively present in nearly all cells in healthy humans and animals. The activity of IL-18 is balanced by the presence of a high affinity, naturally occurring IL-18 binding protein (IL-18BP). In humans, increased disease severity can be associated with an imbalance of IL-18 to IL-18BP such that the levels of free IL-18 are elevated in the circulation. Increasing number of studies have expanded the role of IL-18 in mediating inflammation in animal models of disease using the IL-18BP, IL-18-deficient mice, neutralization of IL-18, or deficiency in the IL-18 receptor alpha chain. A role for IL-18 has been implicated in several autoimmune diseases, myocardial function, emphysema, metabolic syndromes, psoriasis, inflammatory bowel disease, hemophagocytic syndromes, macrophage activation syndrome, sepsis, and acute kidney injury, although in some models of disease, IL-18 is protective. IL-18 plays a major role in the production of interferon-γ from T-cells and natural killer cells. The IL-18BP has been used safely in humans and clinical trials of IL-18BP as well as neutralizing anti-IL-18 antibodies are in clinical trials. This review updates the biology of IL-18 as well as its role in human disease.

Molecular Approach to Adenosine Receptors: Receptor-Mediated Mechanisms of Tissue Protection

Abstract: Adenosine accumulation during ischemia and inflammation protects tissues from injury. In ischemic tissues adenosine accumulates due to inhibition of adenosine kinase, and in inflamed tissues adenos...