Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear hormone receptor that functions as a transcriptional regulator in a variety of tissues. PPARgamma activation, e.g., through binding of the synthetic glitazones or thiazolidinediones (TZD), results in a marked improvement in type 2 diabetic patients of insulin and glucose parameters resulting from an improvement of whole body insulin sensitivity. The role of different metabolic tissues (fat, skeletal muscle, liver) in mediating PPARgamma function in glucose and insulin homeostasis is still unclear. Recently, the function of PPARgamma in adipose tissue and skeletal muscle has been intensively characterized by using targeted deletion of PPARgamma in those tissues. In those studies, adipose PPARgamma has been identified as an essential mediator for the maintainance of whole body insulin sensitivity. Two major mechanisms have been described. 1) Adipose PPARgamma protects nonadipose tissue against excessive lipid overload and maintains normal organ function (liver, skeletal muscle); and 2) adipose PPARgamma guarantees a balanced and adequate production of secretion from adipose tissue of adipocytokines such as adiponectin and leptin, which are important mediators of insulin action in peripheral tissues. In contrast to studies in adipose-specific PPARgamma-deficient mice, the data in muscle-specific PPARgamma(-/-) mice demonstrate that whole body insulin sensitivity is, at least in part, relying on an intact PPARgamma system in skeletal muscle. Finally, these early and elegant studies using tissue-specific PPARgamma knockout mouse models pinpoint adipose tissue as the major target of TZD-mediated improvement of hyperlipidemia and insulin sensitization.
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PMID:PPARgamma-mediated insulin sensitization: the importance of fat versus muscle. 1563 49

The PGC-1 family of coactivators stimulates the activity of certain transcription factors and nuclear receptors. Transcription factors in the sterol responsive element binding protein (SREBP) family are key regulators of the lipogenic genes in the liver. We show here that high-fat feeding, which induces hyperlipidemia and atherogenesis, stimulates the expression of both PGC-1beta and SREBP1c and 1a in liver. PGC-1beta coactivates the SREBP transcription factor family and stimulates lipogenic gene expression. Further, PGC-1beta is required for SREBP-mediated lipogenic gene expression. However, unlike SREBP itself, PGC-1beta reduces fat accumulation in the liver while greatly increasing circulating triglycerides and cholesterol in VLDL particles. The stimulation of lipoprotein transport upon PGC-1beta expression is likely due to the simultaneous coactivation of the liver X receptor, LXRalpha, a nuclear hormone receptor with known roles in hepatic lipid transport. These data suggest a mechanism through which dietary saturated fats can stimulate hyperlipidemia and atherogenesis.
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PMID:Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. 1568 Mar 31

Type 2 diabetes mellitus (T2DM) is highly prevalent chronic disease. Recently, many biological targets are discovered for treatment of this disease. The identification of the nuclear hormone receptor peroxisome proliferator activated receptors (PPAR) and their subtypes alpha, gamma and delta or beta as targets for controlling lipid, glucose and energy homeostasis has proved to be exciting. As hyperlipidaemia, obesity and insulin resistance are independent risk factors for coronary heart disease and macrovascular complications of diabetes; new agents that increase insulin sensitivity as well as decrease hyperlipidaemia by distinct yet complementary mechanism are being studied as they may provide improved therapy for T2DM and related disorders. In this article, we review highly potent PPARgamma agonists, PPARalpha/gamma dual agonists, PPAR pan agonists, alternative PPAR ligands like partial agonists or selective PPAR modulators (SPPARMs) and antagonists from a chemist point of view.
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PMID:Fine tuning of PPAR ligands for type 2 diabetes and metabolic syndrome. 1671 31

Recent studies indicate that the methylation state of histones can be dynamically regulated by histone methyltransferases and demethylases. The H3K9-specific demethylase Jhdm2a (also known as Jmjd1a and Kdm3a) has an important role in nuclear hormone receptor-mediated gene activation and male germ cell development. Through disruption of the Jhdm2a gene in mice, here we demonstrate that Jhdm2a is critically important in regulating the expression of metabolic genes. The loss of Jhdm2a function results in obesity and hyperlipidemia in mice. We provide evidence that the loss of Jhdm2a function disrupts beta-adrenergic-stimulated glycerol release and oxygen consumption in brown fat, and decreases fat oxidation and glycerol release in skeletal muscles. We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. Furthermore, we demonstrate that beta-adrenergic activation-induced binding of Jhdm2a to the PPAR responsive element (PPRE) of the Ucp1 gene not only decreases levels of H3K9me2 (dimethylation of lysine 9 of histone H3) at the PPRE, but also facilitates the recruitment of Ppargamma and Rxralpha and their co-activators Pgc1alpha (also known as Ppargc1a), CBP/p300 (Crebbp) and Src1 (Ncoa1) to the PPRE. Our studies thus demonstrate an essential role for Jhdm2a in regulating metabolic gene expression and normal weight control in mice.
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PMID:Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. 1919 61

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factor belonging to a nuclear hormone receptor superfamily, containing three isoforms (alpha, beta/delta, and gamma). PPARs play a critical physiological role as a primary lipid sensor and regulator of lipid metabolism. Thus, its ligands are clinically used for treatment of type 2 diabetes and hyperlipidemia. On the other hand, PPAR ligands exert the antineuroinflammatory activity through preventing upregulation of inflammatory mediators in animal models for neurodegenerative disease and autoimmune disease. Neuropathic pain and inflammatory pain, clinically important one, are chronically progressed and underlain by neuroinflammation. In a few years, some studies using experimental models emerge that administration of PPAR ligands reduces inflammatory pain and neuropathic pain. PPAR ligands repress expression of genes for inflammatory mediators involved in both pains, such as proinflammatory cytokines, by a molecular mechanism termed ligand-dependent direct transrepression. Alternative mechanism is independent of transcriptional regulation of target genes, such as inhibition of activity of ion channels involved in the development of inflammatory pain and neuropathic pain, and therefore the analgesic effect occurs with rapid onset. The effects of PPAR ligands on neuroinflammation in animal models suggest their possible use for treating human inflammatory pain and neuropathic pain.
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PMID:PPAR and Pain. 1960 69

Children, who are born with low birth weight (less than 2500 g) are known to have an increased risk of developing metabolic syndrome in later live. PPAR could play a regulatory role in the pathogenesis of hyperlipidemia disturbance and a modulatory role in the control of inflammatory response. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of lig and -dependent transcription factors with pleiotropic effects on lipid metabolism, glucose homeostasis, cell proliferation, control of inflammation and atherosclerosis. Three isoforms of PPAR, i.e. a, p, y have been identified and are differentially expressed in various tissues and play different metabolic functions. In this review, the roles of PPAR and their implications in the control of vascular inflammation and atherosclerosis are discussed, especially in the group of risk developing metabolic syndrome -children with low birth weight (below 2500 g).
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PMID:[Roles of PPARs in the origin of metabolic disturbances in children with low birth weight (below 2500 g)]. 1977 18