Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The uncoupling protein-3 (UCP-3) gene encodes for a mitochondrial protein expressed preferentially in skeletal muscle. UCP-3 mRNA is expressed in cultured muscle cells (C2C12 or L6E9) only when differentiated, at which stage UCP-3 is highly induced by all-trans retinoic acid (RA). Here we report that human UCP-3 promoter activity is dependent on MyoD and inducible by all trans-RA. The action of all trans-RA is increased by co-transfection with RA receptor (RAR). We have characterized the RA response element that controls the induction by RA in the 5' noncoding region of the UCP-3 gene. Deletion and point-mutation analysis of the hUCP-3 promoter led us to identify a direct-repeat element with one base-pair spacing (DR1) at position -71/-59 responsible for the induction by RA of the activity of the promoter. This DR1 element bound a nuclear protein complex from muscle cells that contain RAR and retinoid X receptor (RXR). In the absence of this element, the promoter became unresponsive to RA, but it was still dependent on MyoD. In conclusion, it has been established that UCP-3 gene promoter activity is dependent on MyoD, and the first regulatory pathway for UCP-3 gene promoter regulation has been recognized by identifying RA as a transcriptional activator of the gene.
 ...
PMID:The human uncoupling protein-3 gene promoter requires MyoD and is induced by retinoic acid in muscle cells. 1102 1

Malonyl-CoA functions as a mediator in the hypothalamic sensing of energy balance and regulates the neural physiology that governs feeding behavior and energy expenditure. The central administration of C75, a potent inhibitor of the fatty acid synthase (FAS), increases malonyl-CoA concentration in the hypothalamus and suppresses food intake while activating fatty acid oxidation in skeletal muscle. Closely correlated with the increase in muscle fatty acid oxidation is the phosphorylation/inactivation of acetyl-CoA carboxylase, which leads to reduced malonyl-CoA concentration. Lowering muscle malonyl-CoA, a potent inhibitor of carnitine/palmitoyl-CoA transferase 1 (CPT1), releases CPT1 from inhibitory constraint, facilitating the entry of fatty acids into mitochondria for beta oxidation. Also correlated with these events are C75-induced increases in the expression of skeletal muscle peroxisome proliferator-activated receptor alpha (PPARalpha), a transcriptional activator of fatty acid oxidizing enzymes, and uncoupling protein 3 (UCP3), a thermogenic mitochondrial uncoupling protein. Phentolamine, an alpha-adrenergic blocking agent, prevents the C75-induced increases of skeletal muscle UCP3 and whole body fatty acid oxidation and C75-induced decrease of skeletal muscle malonyl-CoA. Thus, the sympathetic nervous system is implicated in the transmission of the "malonyl-CoA signal" from brain to skeletal muscle. Consistent with the up-regulation of UCP3 and PPARalpha is the concomitant increase in the expression of PGC1alpha, transcriptional coactivator of the UCP3 and PPARalpha-activated genes. These findings clarify the mechanism by which the hypothalamic malonyl-CoA signal is communicated to metabolic systems in skeletal muscle that regulate fatty acid oxidation and energy expenditure.
 ...
PMID:Inhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle. 1620 72

Retinoid-related orphan receptor gamma (RORgamma) is an orphan nuclear hormone receptor (NR) that is preferentially expressed in skeletal muscle and several other tissues, including pancreas, thymus, prostate, liver and testis. Surprisingly, the specific role of RORgamma in skeletal muscle, a peripheral tissue, has not been examined. Muscle is one of the most energy demanding tissues which accounts for ~40% of the total body mass and energy expenditure, >75% of glucose disposal and relies heavily on beta-oxidation of fatty acids. We hypothesize that RORgamma regulates metabolism in this major mass lean tissue. This hypothesis was examined by gain and loss of function studies in an in vitro mouse skeletal muscle cell culture model. We show that RORgamma mRNA and protein are dramatically induced during skeletal muscle cell differentiation. We utilize stable ectopic over-expression of VP16-RORgamma (gain of function), native RORgamma and RORgammaDeltaH12 (loss of function) vectors to modulate RORgamma mRNA expression and function. Ectopic VP16 (herpes simplex virus transcriptional activator)-RORgamma and native RORgamma expression increases RORalpha mRNA expression. Candidate-driven expression profiling of lines that ectopically express the native and variant forms of RORgamma suggested that this orphan NR has a function in regulating the expression of genes that control lipid homeostasis (fatty acid-binding protein 4, CD36 (fatty acid translocase), lipoprotein lipase and uncoupling protein 3), carbohydrate metabolism (GLUT5 (fructose transporter), adiponectin receptor 2 and interleukin 15 (IL-15)) and muscle mass (including myostatin and IL-15). Surprisingly, the investigation revealed a function for RORgamma in the pathway that regulates production of reactive oxygen species.
 ...
PMID:Retinoid-related orphan receptor gamma regulates several genes that control metabolism in skeletal muscle cells: links to modulation of reactive oxygen species production. 1760 83