Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.79 (hormone-sensitive lipase)
 2,163 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prolonged exposure of isolated islets to supraphysiologic concentrations of palmitate decreases insulin gene expression in the presence of elevated glucose levels. This study was designed to determine whether or not this phenomenon is associated with a glucose-dependent increase in esterification of fatty acids into neutral lipids. Gene expression of sn-glycerol-3-phosphate acyltransferase (GPAT), diacylglycerol acyltransferase (DGAT), and hormone-sensitive lipase (HSL), three key enzymes of lipid metabolism, was detected in isolated rat islets. Their levels of expression were not affected after a 72-h exposure to elevated glucose and palmitate. To determine the effects of glucose on palmitate-induced neutral lipid synthesis, isolated rat islets were cultured for 72 h with trace amounts of [14C]palmitate with or without 0.5 mmol/l unlabeled palmitate, at 2.8 or 16.7 mmol/l glucose. Glucose increased incorporation of [14C]palmitate into complex lipids. Addition of exogenous palmitate directed lipid metabolism toward neutral lipid synthesis. As a result, neutral lipid mass was increased upon prolonged incubation with elevated palmitate only in the presence of high glucose. The ability of palmitate to increase neutral lipid synthesis in the presence of high glucose was concentration-dependent in HIT cells and was inversely correlated to insulin mRNA levels. 2-Bromopalmitate, an inhibitor of fatty acid mitochondrial beta-oxidation, reproduced the inhibitory effect of palmitate on insulin mRNA levels. In contrast, palmitate methyl ester, which is not metabolized, and the medium-chain fatty acid octanoate, which is readily oxidized, did not affect insulin gene expression, suggesting that fatty-acid inhibition of insulin gene expression requires activation of the esterification pathway. These results demonstrate that inhibition of insulin gene expression upon prolonged exposure of islets to palmitate is associated with a glucose-dependent increase in esterification of fatty acids into neutral lipids.
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PMID:Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. 1127 42

It has been observed previously that hormone-sensitive lipase-deficient (HSL-ko) mice have reduced white adipose tissue (WAT) stores compared to control mice. These findings contradict the expectation that the decreased lipolytic activity in WAT of HSL-ko mice would cause accumulation of triglycerides (TGs) in that tissue. Here we demonstrate that the cellular TG synthesis in HSL-deficient WAT is markedly reduced due to downregulation of the enzymatic activities of glycerophosphate acyltransferase, dihydroxyacetonphosphate acyltransferase, lysophosphatidate acyltransferase, and diacylglycerol acyltransferase. Fatty acid de novo synthesis is also decreased due to reduced cellular glucose uptake, reduced glucose incorporation into adipose tissue lipids, and reduced activities of acetyl:CoA carboxylase and fatty acid synthase. Finally, the activities of phosphoenolpyruvate carboxykinase (PEPCK), acyl:CoA synthetase (ACS), and glucose 6-phosphate dehydrogenase, the enzymes that provide glycerol-3-phosphate, acyl-CoA, and NADPH for TG synthesis, respectively, are decreased in HSL-ko mice. The reduced expression of the peroxisome proliferator-activated receptor gamma (PPAR gamma) target genes PEPCK, ACS, and aP2, as well as reduced mRNA levels of PPAR gamma itself, suggest the involvement of this transcription factor in the downregulation of lipogenesis. Taken together, these results establish that in the absence of HSL, the reduced NEFA production is counteracted by a drastic reduction of NEFA reesterification that provides sufficient quantities of NEFA for release into the circulation. These metabolic adaptations result in decreased fat mass in HSL-ko mice.
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PMID:Decreased fatty acid esterification compensates for the reduced lipolytic activity in hormone-sensitive lipase-deficient white adipose tissue. 1292 28

To elucidate the role of hormone-sensitive lipase (HSL) in diet-induced obesity, HSL-deficient (HSL-/-) and wild-type mice were fed normal chow or high-fat diets. HSL-/- mice were resistant to diet-induced obesity showing higher core body temperatures. Weight and triacylglycerol contents were decreased in white adipose tissue (WAT) but increased in both brown adipose tissue (BAT) and liver of HSL-/- mice. Serum insulin levels in the fed state and tumor necrosis factor-alpha mRNA levels in adipose tissues were higher, whereas serum levels of adipocyte complement-related protein of 30 kDa (ACRP30)/adiponectin and leptin, as well as mRNA levels of ACRP30/adiponectin, leptin, resistin, and adipsin in WAT, were lower in HSL-/- mice than in controls. Expression of transcription factors associated with adipogenesis (peroxisome proliferator-activated receptor-gamma, CAAT/enhancer-binding protein-alpha) and lipogenesis (carbohydrate response element-binding protein, adipocyte determination- and differentiation-dependent factor-1/sterol regulatory element-binding protein-1c), as well as of adipose differentiation markers (adipocyte lipid-binding protein, perilipin, lipoprotein lipase), lipogenic enzymes (glycerol-3-phosphate acyltransferase, acyl-CoA:diacylglycerol acyltransferase-1 and -2, fatty acid synthase, ATP citrate lyase) and insulin signaling proteins (insulin receptor, insulin receptor substrate-1, GLUT4), was suppressed in WAT but not in BAT of HSL-/- mice. In contrast, expression of genes associated with cholesterol metabolism (sterol-regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA:cholesterol acyltransferase-1) and thermogenesis (uncoupling protein-2) was upregulated in both WAT and BAT of HSL-/- mice. Our results suggest that impaired lipolysis in HSL deficiency affects lipid metabolism through alterations of adipose differentiation and adipose-derived hormone levels.
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PMID:Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice. 1295 98

It was hypothesized that transcriptional reprogramming is involved in the structural and functional adaptations of lipid metabolism in human tibialis anterior muscle (TA) from endurance-trained male subjects. RT-PCR experiments demonstrated a significant upregulation of the mRNA level of key enzymes involved in 1) lipolytic mobilization of fatty acids (FA) from intramyocellular lipid (IMCL) stores via hormone-sensitive lipase (LIPE), 2) intramyocellular FA transport via muscle fatty acid binding protein (FABP3), and 3) oxidative phosphorylation (cytochrome c oxidase I, COI), in TA of endurance-trained vs. untrained subjects. In contrast, mRNAs for factors involved in glycolysis (muscle 6-phosphofructokinase, PFKM), intramyocellular storage of FA (diacylglycerol O-acyltransferase 1, DGAT), and beta-oxidation (long-chain acyl-coenzyme A dehydrogenase, ACADL) were invariant between TA of trained and untrained subjects. Correlation analysis identified an association of LIPE with FABP3 and LPL (lipoprotein lipase) mRNA levels and indicated coregulation of the transcript level for LIPE, FABP3, and COI with the level of mRNA encoding peroxisome proliferator-activated receptor-alpha (PPAR-alpha), the master regulator of lipid metabolism. Moreover, a significant correlation existed between LPL mRNA and the absolute rate of IMCL repletion determined by magnetic resonance spectroscopy after exhaustive exercise. Additionally, the LIPE mRNA level correlated with ultrastructurally determined IMCL content and mitochondrial volume density. The present data point to a training-induced, selective increase in mRNA levels of enzymes which are involved in metabolization of intramuscular FA, and these data confirm the well-established phenomenon of enhanced lipid utilization during exercise at moderate intensity in muscles of endurance-trained subjects.
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PMID:Transcriptional adaptations of lipid metabolism in tibialis anterior muscle of endurance-trained athletes. 1456 68

The aim of this study was to evaluate the morphometric changes of adipose tissue of lean and obese rats as assessed by computerized image analysis (IA) system in experimental conditions, with different degrees of adiposity. Moreover, to validate measures obtained by image analysis by correlation with direct measures of adiposity (body weight, epididimal fat, mean fat cell size and serum leptin). Finally to correlate these changes to expression of genes involved in lipid deposition and mobilization in adipose tissue. Lean (Fa/?) and genetically obese (fa/fa) Zucker rats were studied. Obese rats were food-restricted or treated with retinoic acid (ATRA) in order to reduce body weight and fat content. Moreover, gene expression of two key enzymes involved in fat metabolism (HSL and DGAT) were assessed in adipose tissue by RT-PCR. Our results show that HSL expression in adipose tissue was lower in obese compared to lean rats (1.47+/-0.02 vs 0.35+/-0.03, p<0.005) and was upregulated during food restriction in obese rats. DGAT expression was similar in lean and obese rats and was reduced by treatment with ATRA in obese rats. Tissue texture assessed by IA was significantly higher in lean compared to obese rats (23.2+/-0.6 vs 11.6+/-2.4%; p=0.01). Tissue structure highly correlated with adiposity in obese rats with different amount of body fat (area fraction vs epididimal fat depot: p=0.001). Distribution of measures for each sample, an index of spread of adipose tissue texture, as expressed by the standard deviation, correlated with adiposity (standard deviation vs epididimal fat depot: p=0.002) thus suggesting that adipose tissue texture increases its heterogeneity when adiposity is lower. This observation is in agreement with the hypothesis that the process of lipid mobilization from adipose tissue is not uniform, but a subpopulation of slimming adipocytes undergoes a complete release of their fat content while the rest of the tissue is much less affected. Moreover, image analysis system seems a reliable quantitative tool for assessment of adipose tissue texture.
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PMID:Molecular and morphometric description of adipose tissue during weight changes: a quantitative tool for assessment of tissue texture. 1549 63

Fatty acid-binding proteins (FABPs) facilitate the diffusion of fatty acids within cellular cytoplasm. Compared with C57Bl/6J mice maintained on a high-fat diet, adipose-FABP (A-FABP) null mice exhibit increased fat mass, decreased lipolysis, increased muscle glucose oxidation, and attenuated insulin resistance, whereas overexpression of epithelial-FABP (E-FABP) in adipose tissue results in decreased fat mass, increased lipolysis, and potentiated insulin resistance. To identify the mechanisms that underlie these processes, real-time PCR analyses indicate that the expression of hormone-sensitive lipase is reduced, while perilipin A is increased in A-FABP/aP2 null mice relative to E-FABP overexpressing mice. In contrast, de novo lipogenesis and expression of genes encoding lipoprotein lipase, CD36, long-chain acyl-CoA synthetase 5, and diacylglycerol acyltransferase are increased in A-FABP/aP2 null mice relative to E-FABP transgenic animals. Consistent with an increase in de novo lipogenesis, there was an increase in adipose C16:0 and C16:1 acyl-CoA pools. There were no changes in serum free fatty acids between genotypes. Serum levels of resistin were decreased in the E-FABP transgenic mice, whereas serum and tissue adiponectin were increased in A-FABP/aP2 null mice and decreased in E-FABP transgenic animals; leptin expression was unaffected. These results suggest that the balance between lipolysis and lipogenesis in adipocytes is remodeled in the FABP null and transgenic mice and is accompanied by the reprogramming of adipokine expression in fat cells and overall changes in plasma adipokines.
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PMID:Lipid metabolism and adipokine levels in fatty acid-binding protein null and transgenic mice. 1630 44

Prp19p is an integral component of the heteromeric protein complex (the NineTeen complex) in the nucleus, and it is essential for the structural integrity of NineTeen complex and its subsequent activation of the spliceosome. We identified Prp19p, which has never been reported in relation to any function outside of the nucleus, as a member of proteins associated with lipid droplets. Down-regulation of Prp19p expression with RNA interference in 3T3-L1 cells repressed lipid droplet formation with the reduction in the level of expression of perilipin and S3-12. The levels of expression of SCD1 (stearoyl-CoA desaturase-1), DGAT-1 (acyl-CoA diacylglycerol acyltransferase-1), and glycerol-3-phosphate acyltransferase were also reduced in Prp19p down-regulated cells, and a significant decrease in triglycerides was observed. Unlike perilipin, which is one of the most extensively studied lipid droplet-associated proteins, Prp19p is not essential for cAMP- and hormone-sensitive lipase-dependent lipolysis pathways, even though Prp19p is a component of the lipid droplet phospholipid monolayer, and down-regulation of Prp19p represses fat accretion significantly. These results suggest that Prp19p or Prp19-interacting proteins during lipid droplet biogenesis in adipocytes may be considered as another class of potential targets for attacking obesity and obesity-related problems.
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PMID:Identification of mouse Prp19p as a lipid droplet-associated protein and its possible involvement in the biogenesis of lipid droplets. 1711 36

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of abnormal liver dysfunction, and its prevalence has markedly increased. We previously evaluated the expression of fatty acid metabolism-related genes in NAFLD and reported changes in expression that could contribute to increased fatty acid synthesis. In the present study, we evaluated the expression of additional fatty acid metabolism-related genes in larger groups of NAFLD (n=26) and normal liver (n=10) samples. The target genes for real-time PCR analysis were as follows: acetyl-CoA carboxylase (ACC) 1, ACC2, fatty acid synthase (FAS), sterol regulatory element-binding protein 1c (SREBP-1c), and adipose differentiation-related protein (ADRP) for evaluation of de novo synthesis and uptake of fatty acids; carnitine palmitoyltransferase 1a; (CPT1a), long-chain acyl-CoA dehydrogenase (LCAD), long-chain L-3-hydroxyacylcoenzyme A dehydrogenase alpha (HADHalpha), uncoupling protein 2 (UCP2), straight-chain acyl-CoA oxidase (ACOX), branched-chain acyl-CoA oxidase (BOX), cytochrome P450 2E1 (CYP2E1), CYP4A11, and peroxisome proliferator-activated receptor (PPAR)alpha for oxidation in the mitochondria, peroxisomes and microsomes; superoxide dismutase (SOD), catalase, and glutathione synthetase (GSS) for antioxidant pathways; and diacylglycerol O-acyltransferase 1 (DGAT1), PPARgamma, and hormone-sensitive lipase (HSL) for triglyceride synthesis and catalysis. In NAFLD, although fatty acids accumulated in hepatocytes, their de novo synthesis and uptake were up-regulated in association with increased expression of ACC1, FAS, SREBP-1c, and ADRP. Fatty acid oxidation-related genes, LCAD, HADHalpha, UCP2, ACOX, BOX, CYP2E1, and CYP4A11, were all overexpressed, indicating that oxidation was enhanced in NAFLD, whereas the expression of CTP1a and PPARalpha was decreased. Furthermore, SOD and catalase were also overexpressed, indicating that antioxidant pathways are activated to neutralize reactive oxygen species (ROS), which are overproduced during oxidative processes. The expression of DGAT1 was up-regulated without increased PPARgamma expression, whereas the expression of HSL was decreased. Our data indicated the following regarding NAFLD: i) increased de novo synthesis and uptake of fatty acids lead to further fatty acid accumulation in hepatocytes; ii) mitochondrial fatty acid oxidation is decreased or fully activated; iii) in order to complement the function of mitochondria (beta-oxidation), peroxisomal (beta-oxidation) and microsomal (omega-oxidation) oxidation is up-regulated to decrease fatty acid accumulation; iv) antioxidant pathways including SOD and catalase are enhanced to neutralize ROS overproduced during mitochondrial, peroxisomal, and microsomal oxidation; and v) lipid droplet formation is enhanced due to increased DGAT expression and decreased HSL expression. Further studies will be needed to clarify how fatty acid synthesis is increased by SREBP-1c, which is under the control of insulin and AMP-activated protein kinase.
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PMID:Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. 1767 40

1. Insulin resistance occurs when normal amounts of insulin are inadequate to produce a normal insulin response from cells. This is important in the context of whole-body glucose homeostasis because skeletal muscle is the main tissue for insulin-stimulated glucose disposal. 2. In obesity, lipid deposition in peripheral tissues, such as skeletal muscle, is linked to the activation of stress kinases and the development of insulin resistance. Accumulation of intramyocellular triglyceride (IMTG) is positively associated with insulin resistance; however, it is unknown whether IMTG causes insulin resistance or protects cells from insulin resistance by preventing the accrual of bioactive lipid metabolites. 3. The role of IMTG in the development of insulin resistance is not resolved. Stable overexpression of the triglyceride lipase adipose triglyceride lipase (ATGL) reduced IMTG content in myotubes, but resulted in a concomitant increase in diacylglycerol (DAG) and ceramide and caused insulin resistance. Increasing TG content by muscle-specific overexpression of diacylglycerol acyltransferase (DGAT) 1 protected mice from insulin resistance. Conversely, overexpression of DGAT2 in glycolytic muscle resulted in accumulation of TG and ceramide and insulin resistance in these tissues. This was sufficient to induce whole-body insulin and glucose insensitivity. 4. It is unlikely that IMTG causes cause insulin resistance directly. Instead, it appears as though TG accumulates in skeletal muscle to sequester fatty acids and to protect from the deleterious actions of lipids, such as ceramide and DAG. Whether lipase inhibitors are viable therapeutics to prevent obesity induced insulin resistance is unknown, but future studies examining tissue-specific ATGL/hormone-sensitive lipase knockouts will hopefully resolve this question.
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PMID:Storing up trouble: does accumulation of intramyocellular triglyceride protect skeletal muscle from insulin resistance? 1898 21

In order to study the mechanism of monoclonal antibody (McAb) against a porcine 40-kDa adipocyte-specific plasma membrane protein in reducing fat deposition, porcine primary adipocytes were treated with the McAb during the process of adipocyte differentiation; its effect on expression of lipid metabolism related genes was investigated. Adipocytes were treated with 1-methyl-3-isobutylmethylxanthine (IDX) plus 10 microg/mL of the McAb or without McAb. The mRNA levels of adipocyte differentiation related genes (PPARgamma and C/EBPalpha), lipid metabolism related genes (FAS, HSL, CPT-1B, DGAT and A-FABP) and adiponectin gene (AdipoQ) were determined using real-time quantitative PCR. The results showed that the differentiated adipocyte number and triglyceride (TG) content in adipocytes treated with the McAb were lower than that in cells without McAb during the whole process of adipocyte differentiation. The McAb significantly reduced mRNA expression of PPARgamma, C/EBPalpha, FAS, DGAT, A-FABP and adiponectin genes, but increased mRNA expression of HSL and CPT-1B genes during the medium and latter stage of adipocyte differentiation. This suggested that the McAb decreased triglycerol accumulation in adipocyte by both inhibiting adipocyte differentiation and regulating lipid metabolism, especially at the medium and latter stage of porcine adipocyte differentiation.
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PMID:Effect of monoclonal antibody on expression of lipid metabolism related genes in porcine adipocytes. 1975 70


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