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)

Noninsulin-dependent diabetes mellitus (NIDDM), a major health care problem in the Western world, is a disease typified by a relative deficiency of insulin, leading to vast derangements in glucose and lipid homeostasis with disastrous vascular complications. Despite immense research efforts aimed at a clear understanding of the etiology of this complex disease, the molecular mechanisms causing the disorder still remain elusive. This article reviews extant data from recent publications implicating novel signal transduction pathways as important regulators of the insulin stimulus-secretion coupling in the pancreatic beta-cell. The significance of nitric oxide and serine/threonine protein phosphatases, and their inactivation by insulin secretagogues, glucose metabolites, ATP, GTP, glutamate, and inositol hexaphosphate in this arena is scrutinized. Additionally, also presented is the growing concept that an important signal for insulin secretion may reside in the inextricable interplay between glucose and lipid metabolism, specifically the generation of malonyl-CoA, which inhibits carnitine palmitoyltransferase 1 with the attendant accumulation of long-chain acyl CoA esters. Moreover, attention is directed towards novel intracellular actions of hypoglycemic sulfonylureas in the beta-cell. Finally, the importance of "lipotoxicity" and aberrations in glucose uptake and metabolism in beta-cell dysfunction is given consideration. Future research efforts should aim at further characterization of effects of second messengers on protein phosphorylation elements in beta-cells. Additionally, long-term regulation by glucose and the diabetic state (e.g., fatty acids and ketones) on beta-cell protein phosphatases, pyruvate dehydrogenase, and carnitine palmitoyltransferase 1 needs to be explored in greater depth. Clearly, the detrimental impact of diabetic hyperlipidemia on beta-cell function has been a relatively neglected area, but futu re pharmacological approaches directed at preventing lipotoxicity may prove beneficial in the treatment of diabetes.
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PMID:Aspects of novel sites of regulation of the insulin stimulus-secretion coupling in normal and diabetic pancreatic islets. 979 25

Beta-cells possess inherent mechanisms to adapt to overnutrition and the prevailing concentrations of glucose, fatty acids, and other fuels to maintain glucose homeostasis. However, this is balanced by potentially harmful actions of the same nutrients. Both glucose and fatty acids may cause good/adaptive or evil/toxic actions on the beta-cell, depending on their concentrations and the time during which they are elevated. Chronic high glucose dramatically influences beta-cell lipid metabolism via substrate availability, changes in the activity and expression of enzymes of glucose and lipid metabolism, and modifications in the expression level of key transcription factors. We discuss here the emerging view that beta-cell "glucotoxicity" is in part indirectly caused by "lipotoxicity," and that beta-cell abnormalities will become particularly apparent when both glucose and circulating fatty acids are high. We support the concept that elevated glucose and fatty acids synergize in causing toxicity in islets and other organs, a process that may be instrumental in the pleiotropic defects associated with the metabolic syndrome and type 1 and type 2 diabetes. The mechanisms by which hyperglycemia and hyperlipidemia alter insulin secretion are discussed and a model of beta-cell "glucolipotoxicity" that implicates alterations in beta-cell malonyl-CoA concentrations; peroxisome proliferator-activated receptor-alpha and -gamma and sterol regulatory element binding protein-1c expression; and lipid partitioning is proposed.
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PMID:Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. 1247 83

NADPH is an essential cofactor for many enzymatic reactions including glutathione metabolism and fat and cholesterol biosynthesis. We have reported recently an important role for mitochondrial NADP(+)-dependent isocitrate dehydrogenase in cellular defense against oxidative damage by providing NADPH needed for the regeneration of reduced glutathione. However, the role of cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDPc) is still unclear. We report here for the first time that IDPc plays a critical role in fat and cholesterol biosynthesis. During differentiation of 3T3-L1 adipocytes, both IDPc enzyme activity and its protein content were increased in parallel in a time-dependent manner. Increased expression of IDPc by stable transfection of IDPc cDNA positively correlated with adipogenesis of 3T3-L1 cells, whereas decreased IDPc expression by an antisense IDPc vector retarded adipogenesis. Furthermore, transgenic mice with overexpressed IDPc exhibited fatty liver, hyperlipidemia, and obesity. In the epididymal fat pads of the transgenic mice, the expressions of adipocyte-specific genes including peroxisome proliferator-activated receptor gamma were markedly elevated. The hepatic and epididymal fat pad contents of acetyl-CoA and malonyl-CoA in the transgenic mice were significantly lower, whereas the total triglyceride and cholesterol contents were markedly higher in the liver and serum of transgenic mice compared with those measured in wild type mice, suggesting that the consumption rate of those lipogenic precursors needed for fat biosynthesis must be increased by elevated IDPc activity. Taken together, our findings strongly indicate that IDPc would be a major NADPH producer required for fat and cholesterol synthesis.
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PMID:Cytosolic NADP+-dependent isocitrate dehydrogenase plays a key role in lipid metabolism. 1525 34

Nitric oxide (NO) is synthesized from L-arginine by NO synthase in virtually all cell types. Emerging evidence shows that NO regulates the metabolism of glucose, fatty acids and amino acids in mammals. As an oxidant, pathological levels of NO inhibit nearly all enzyme-catalyzed reactions through protein oxidation. However, as a signaling molecule, physiological levels of NO stimulate glucose uptake as well as glucose and fatty acid oxidation in skeletal muscle, heart, liver and adipose tissue; inhibit the synthesis of glucose, glycogen, and fat in target tissues (e.g., liver and adipose); and enhance lipolysis in adipocytes. Thus, an inhibition of NO synthesis causes hyperlipidemia and fat accretion in rats, whereas dietary arginine supplementation reduces fat mass in diabetic fatty rats. The putative underlying mechanisms may involve multiple cyclic guanosine-3',5'-monophosphate-dependent pathways. First, NO stimulates the phosphorylation of adenosine-3',5'-monophosphate-activated protein kinase, resulting in (1) a decreased level of malonyl-CoA via inhibition of acetyl-CoA carboxylase and activation of malonyl-CoA decarboxylase and (2) a decreased expression of genes related to lipogenesis and gluconeogenesis (glycerol-3-phosphate acyltransferase, sterol regulatory element binding protein-1c and phosphoenolpyruvate carboxykinase). Second, NO increases the phosphorylation of hormone-sensitive lipase and perilipins, leading to the translocation of the lipase to the neutral lipid droplets and, hence, the stimulation of lipolysis. Third, NO activates expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, thereby enhancing mitochondrial biogenesis and oxidative phosphorylation. Fourth, NO increases blood flow to insulin-sensitive tissues, promoting substrate uptake and product removal via the circulation. Modulation of the arginine-NO pathway through dietary supplementation with L-arginine or L-citrulline may aid in the prevention and treatment of the metabolic syndrome in obese humans and companion animals, and in reducing unfavorable fat mass in animals of agricultural importance.
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PMID:Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. 1652 13

Since over-nutrition accelerates the development of obesity, progression to type 2 diabetes, and the associated co-morbidity and mortality, there has been a keen interest in therapeutic interventions targeting mechanisms that may curb appetite, increase energy expenditure or at least attenuate insulin resistance. Over the past decade, numerous peri-mitochondrial targets in the de novo lipid synthesis pathway have been linked to an increase in energy expenditure and the drug development industry has pursued the gene products involved as candidates to develop drugs against. The basis of this link, and specifically the premise that lowering tissue and cellular malonyl-CoA can increase energy expenditure, is scrutinised here. The argument presented is that fuel switching as effected by changes in cellular malonyl-CoA concentrations will not trigger the mitochondria to increase energy expenditure because: (1) an increase in beta-oxidation by lowering respiratory exchange ratio (indicative of the metabolic fuel consumed) does not equal an increase in energy expenditure (how rapidly fuel is consumed); (2) the ATP:oxygen ratios (i.e. ATP energy made:oxygen required for the reaction) are similar when metabolising lipids (2.8) vs glucose (3.0); (3) substrate availability (NEFA) does not drive energy expenditure in vivo; and (4) the availability of ADP in the mitochondrial matrix determines the rate of energy expenditure, not the availability of fuel to enter the mitochondrial matrix. To increase mitochondrial energy expenditure, work must be done (exercise) and/or the mitochondrial proton leak must be enhanced, both of which increase availability of ADP. In fact, despite the historic taboo of chemical uncoupling, this mechanism validated in humans is closest on task to increasing whole-body energy expenditure. Chemical uncoupling mimics the naturally occurring phenomenon of proton leak, accelerating the metabolism of glucose and lipids. However, it is completely non-genomic (i.e. the target is a location, not a gene product) and is not associated with addiction or mood alterations common to satiety agents. A significant hurdle for drug development is to discover a safe mitochondrial uncoupler and to formulate it potentially as a pro-drug and/or oral pump, to avoid the issue of overdosing experienced in the 1930s. The potential therapeutic impact of such a compound for an over-nutritioned patient population could be profound. If effective, the mitochondrial uncoupler mechanism could resolve many of the associated diseases such as type 2 diabetes, hypertension, obesity, depression, sleep apnoea, non-alcoholic steatohepatitis, insulin resistance and hyperlipidaemia, therefore becoming a 'disease-modifying therapy'.
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PMID:Targeting energy expenditure via fuel switching and beyond. 2095 61

Significant advances have been made in deciphering the mechanisms underlying fuel-stimulated insulin secretion by pancreatic beta cells. The contribution of the triggering/ATP-sensitive potassium (KATP)-dependent Ca2+ signalling and KATP-independent amplification pathways, that include anaplerosis and lipid signalling of glucose-stimulated insulin secretion (GSIS), are well established. A proposed model included a key role for a metabolic partitioning 'switch', the acetyl-CoA carboxylase (ACC)/malonyl-CoA/carnitine palmitoyltransferase-1 (CPT-1) axis, in beta cell glucose and fatty acid signalling for insulin secretion. This model has gained overwhelming support from a number of studies in recent years and is now refined through its link to the glycerolipid/NEFA cycle that provides lipid signals through its lipolysis arm. Furthermore, acetyl-CoA carboxylase may also control beta cell growth. Here we review the evidence supporting a role for the ACC/malonyl-CoA/CPT-1 axis in the control of GSIS and its particular importance under conditions of elevated fatty acids (e.g. fasting, excess nutrients, hyperlipidaemia and diabetes). We also document how it is linked to a more global lipid signalling system that includes the glycerolipid/NEFA cycle.
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PMID:Lipid-associated metabolic signalling networks in pancreatic beta cell function. 3142 51