Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Ageing is associated with a diminished ability to use fat as a fuel during exercise. Also, middle-aged subjects have a blunted ability to mobilize fatty acids and to increase skeletal muscle fatty acid uptake and oxidation during intravenous beta-adrenergic stimulation, indicating that the sympathetic nervous system may play a role in the disturbed fat utilization. The blunted lipolytic response may be related to disturbances at the receptor level, eg a diminished number or agonist affinity of beta-adrenoceptors, or at the postreceptor level, eg a diminished activity of the hormone-sensitive lipase complex. As the rates of fatty acid availability are not limiting during exercise or beta-adrenergic stimulation in the elderly, the lowered skeletal muscle fat oxidation is probably related to an age-related decline in the capacity of skeletal muscle to oxidize fatty acids. Factors responsible for this decline may be a diminished content of oxidative enzymes, an increased glycolytic flux inhibiting fatty acid transport into the mitochondria, or a diminished (possibly beta-adrenergically-mediated) activation of fatty acid transport. It remains to be determined to what extent disturbances of fat metabolism may be related to the ageing process per se or whether they are secondary to age-related changes in body fat distribution and level of physical activity. Nevertheless, the impairments in sympathetically mediated lipolysis and fat oxidation may be of importance in the age-related increase in adiposity and insulin resistance and may thus be one of the links between ageing and increased prevalence of chronic diseases, such as obesity, type 2 diabetes mellitus, and cardiovascular disease.
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PMID:Adrenergically stimulated fat utilization and ageing. 1102 83

We investigated the mechanisms that lead to combined hyperlipidemia in transgenic mice that overexpress human apolipoprotein (apo) A-II (line 11.1). The 11.1 transgenic mice develop pronounced hypertriglyceridemia, and a moderate increase in free fatty acid (FFA) and plasma cholesterol, especially when fed a high-fat/high-cholesterol diet. Post-heparin plasma lipoprotein lipase and hepatic lipase activities (using artificial or natural autologous substrates), the decay of plasma triglycerides with fasting, and the fractional catabolic rate of the radiolabeled VLDL-triglyceride (both fasting and postprandial) were similar in 11. 1 transgenic mice and in control mice. In contrast, a 2.5-fold increase in hepatic VLDL-triglyceride production was observed in 11. 1 transgenic mice in a period of 2 h in which blood lipolysis was inhibited. This increased synthesis of hepatic VLDL-triglyceride used preformed FFA rather than FFA of de novo hepatic synthesis. The 11.1 transgenic mice also presented reduced epididymal/parametrial white adipose tissue weight (1.5-fold), increased rate of epididymal/parametrial hormone-sensitive lipase-mediated lipolysis (1.2-fold) and an increase in cholesterol and, especially, in triglyceride liver content, suggesting an enhanced mobilization of fat as the source of preformed FFA reaching the liver. Increased plasma FFA was reverted by insulin, demonstrating that 11.1 transgenic mice are not insulin resistant. We conclude that the overexpression of human apoA-II in transgenic mice induces combined hyperlipidemia through an increase in VLDL production. These mice will be useful in the study of molecular mechanisms that regulate the overproduction of VLDL, a situation of major pathophysiological interest since it is the basic mechanism underlying familial combined hyperlipidemia.
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PMID:Increased production of very-low-density lipoproteins in transgenic mice overexpressing human apolipoprotein A-II and fed with a high-fat diet. 1108 33

LiSa-2 is a stable cell line derived from a poorly differentiated, pleomorphic liposarcoma. In serum-containing medium, LiSa-2 cells are fibroblastoid and rapidly dividing. In a serum-free, chemically defined culture medium containing physiological concentrations of insulin, triiodothyronine and cortisol, LiSa-2 cells divide slower and, extensively storing fat, acquire adipocyte morphology. In contrast to fibroblastoid LiSa-2 cells, these adipocyte-like LiSa-2 cells highly express transcripts for peroxisome proliferator-activated receptor-gamma, lipoprotein lipase, fatty acid synthetase, hormone-sensitive lipase, adipocyte most abundant gene transcript-1, glycerol-3-phosphate-dehydrogenase and the insulin-sensitive glucose transporter-4, all of which are specific for differentiated adipocytes. However, leptin mRNA expression was demonstrated only after preventing DNA methylation by incorporation of 5-aza-deoxycytidine into cellular DNA. Functionally, adipocyte-like LiSa-2 cells show increased insulin-dependent glucose uptake and lipid synthesis and are sensitive to lipolytic agents. This cell line may serve as an in vitro model for studying the regulation of human liposarcoma differentiation and for screening drugs for induction of differentiation-associated growth arrest in liposarcomas.
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PMID:LiSa-2, a novel human liposarcoma cell line with a high capacity for terminal adipose differentiation. 1109 10

A lipolytic domain (AOD9401) of human growth hormone (hGH) which resides in the carboxyl terminus of the molecule and contains the amino acid residues 177-191, has been synthesized using solid-phase peptide synthesis techniques. AOD9401 stimulated hormone-sensitive lipase and inhibited acetyl coenzyme A carboxylase (acetyl CoA carboxylase) in isolated rat adipose tissues, in a similar manner to the actions of the intact hGH molecule. The synthetic lipolytic domain mimicked the effect of the intact growth hormone on diacylglycerol release in adipocytes. Chronic treatment of obese Zucker rats with AOD9401 for 20 days reduced the body weight gain of the animals, and the average cell size of the adipocytes of the treated animals decreased from 110 to 80 microm in diameter. Unlike hGH, synthetic AOD9401 did not induce insulin resistance or glucose intolerance in the laboratory animals after chronic treatment. The results suggest that AOD9401 has the potential to be developed into a therapeutic agent for the control of obesity.
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PMID:Molecular and cellular actions of a structural domain of human growth hormone (AOD9401) on lipid metabolism in Zucker fatty rats. 1111 8

Type 2 diabetes is a heterogeneous condition that is not attributable to a single pathophysiological mechanism. In general, both insulin resistance and impaired insulin secretion are required for the disease to become manifest. Thus, as long as the pancreatic beta cells can compensate for the degree of insulin resistance, glucose tolerance remains normal. Clustering of type 2 diabetes in certain families and ethnic populations points to a strong genetic background for the disease. However, environmental factors such as obesity and a sedentary lifestyle are usually required to unmask the genes. Impaired insulin-stimulated glucose metabolism (particularly non-oxidative) in skeletal muscle represents a key feature of type 2 diabetes and is observed early in the pre-diabetic state. It is not clear, though, whether this represents an inherited defect in muscle or whether it develops secondarily, for example, to abdominal obesity. In favour of the latter hypothesis are findings that abdominal obesity and a low metabolic rate seem to precede the development of insulin resistance in offspring of type 2 diabetic patients. According to the thrifty gene hypothesis, individuals living in an environment with an unstable food supply could increase their probability of survival if they could maximize storage of surplus energy, for instance, as abdominal fat. Exposing this energy-storing genotype to the abundance of food typical of westernized societies is detrimental, causing insulin resistance and, subsequently, type 2 diabetes. There are a number of potential thrifty genes, including those that regulate lipolysis or code for the beta3-adrenergic receptor, the hormone-sensitive lipase, and lipoprotein lipase. Type 2 diabetes develops as a consequence of a collision between thrifty genes and a hostile affluent environment. Insulin resistance is a key trigger for the disease, and optimal management of type 2 diabetes should therefore aim to ameliorate insulin resistance early.
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PMID:Insulin resistance: the fundamental trigger of type 2 diabetes. 1122 Feb 83

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

Leptin is produced in adipose tissue and acts in the hypothalamus to regulate food intake. However, recent evidence also indicates a potential for direct roles for leptin in peripheral tissues, including those of the immune system. In this study, we provide direct evidence that macrophages are a target tissue for leptin. We found that J774.2 macrophages express the functional long form of the leptin receptor (ObRb) and that this becomes tyrosine-phosphorylated after stimulation with low doses of leptin. Leptin also stimulates both phosphoinositide 3-kinase (PI 3-kinase) activity and tyrosine phosphorylation of JAK2 and STAT3 in these cells. We investigated the effects of leptin on hormone-sensitive lipase (HSL), which acts as a neutral cholesterol esterase in macrophages and is a rate-limiting step in cholesterol ester breakdown. Leptin significantly increased HSL activity in J774.2 macrophages, and these effects were additive with the effects of cAMP and were blocked by PI 3-kinase inhibitors. Conversely, insulin inhibited HSL in macrophages, but unlike adipocytes, this effect did not require PI 3-kinase. These results indicate that leptin and insulin regulate cholesterol-ester homeostasis in macrophages and, therefore, defects in this process caused by leptin and/or insulin resistance could contribute to the increased incidence of atherosclerosis found associated with obesity and type 2 diabetes.
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PMID:Insulin and leptin acutely regulate cholesterol ester metabolism in macrophages by novel signaling pathways. 1133 38

To clarify the roles of insulin receptor substrate (IRS) family proteins in phosphatidylinositol (PI) 3-kinase activation and insulin actions in adipocytes, we investigated the intracellular localization of IRS family proteins and PI 3-kinase activation in response to insulin by fractionation of mouse adipocytes from wild-type and IRS-1 null mice. In adipocytes from wild-type mice, tyrosine-phosphorylated IRS-1 and IRS-2, which were found to associate with PI 3-kinase in response to insulin, were detected in the plasma membrane (PM) and low-density microsome (LDM) fractions. By contrast, tyrosine-phosphorylated IRS-3 (pp60), which was found to associate with PI 3-kinase, was predominantly localized in the PM fraction. In adipocytes from IRS-1-null mice, insulin-stimulated PI 3-kinase activity in anti-phosphotyrosine (alphaPY) immunoprecipitates in the LDM fraction was almost exclusively mediated via IRS-2 and was reduced to 25%; however, insulin-stimulated PI 3-kinase activity in the PM fraction was primarily mediated via IRS-3 and was reduced to 60%. To determine the potential functional impact of the distinct subcellular localization of IRSs and associating PI 3-kinase activity on adipocyte-specific metabolic actions, we examined lipolysis in IRS-1 null mice. The level of isoproterenol-induced lipolysis was increased 5.1-fold in adipocytes from IRS-1 null mice as compared with wild-type mice. Moreover, hormone-sensitive lipase (HSL) protein was increased 4.3-fold in adipocytes from IRS-1-null mice compared with wild-type mice, and HSL mRNA expression was also increased. The antilipolytic effect of insulin in IRS-1 null adipocytes, however, was comparable to that in wild-type mice. Thus, discordance between these two insulin actions as well as the transcriptional and translational effect (HSL mRNA and protein regulation) and the PM effect (antilipolysis) of insulin may be explained by distinct roles of both PI 3-kinase activity associated with IRS-1/IRS-2 and PI 3-kinase activity associated with IRS-3 in insulin actions related to their subcellular localization.
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PMID:Subcellular localization of insulin receptor substrate family proteins associated with phosphatidylinositol 3-kinase activity and alterations in lipolysis in primary mouse adipocytes from IRS-1 null mice. 1137 48

In the current study, we have determined the cDNA and the genomic sequences of the arylacetamide deacetylase (AADA) gene in mice and rats. The AADA genes in the rat and mouse consist of five exons and have 2.4 kilobases of homologous promoter sequence upstream of the initiating ATG codon. AADA mRNA is expressed in hepatocytes, intestinal mucosal cells (probably enterocytes), the pancreas and also the adrenal gland. In mice, there is a diurnal rhythm in hepatic AADA mRNA concentration, with a maximum 10 h into the light (post-absorptive) phase. This diurnal regulation is attenuated in peroxisome proliferator-activated receptor alpha knockout mice. Intestinal but not hepatic AADA mRNA was increased following oral administration of the fibrate, Wy-14,643. The homology of AADA with hormone-sensitive lipase and the tissue distribution of AADA are consistent with the view that AADA plays a role in promoting the mobilization of lipids from intracellular stores and in the liver for assembling VLDL. This hypothesis is supported by parallel changes in AADA gene expression in animals with insulin-deficient diabetes and following treatment with orotic acid.
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PMID:Characterization of the rodent genes for arylacetamide deacetylase, a putative microsomal lipase, and evidence for transcriptional regulation. 1148 20

Endogenous lipid stores are thought to be involved in the mechanism whereby the beta-cell adapts its secretory capacity in obesity and diabetes. In addition, hormone-sensitive lipase (HSL) is expressed in beta-cells and may provide fatty acids necessary for the generation of coupling factors linking glucose metabolism to insulin release. We have recently created HSL-deficient mice that were used to directly assess the role of HSL in insulin secretion and action. HSL(-/-) mice were normoglycemic and normoinsulinemic under basal conditions, but showed an approximately 30% reduction of circulating free fatty acids (FFAs) with respect to control and heterozygous animals after an overnight fast. An intraperitoneal glucose tolerance test revealed that HSL-null mice were glucose-intolerant and displayed a lack of a rise in plasma insulin after a glucose challenge. Examination of plasma glucose during an insulin tolerance test suggested that HSL-null mice were insulin-resistant, because plasma glucose was barely lowered after the injection of insulin. Freshly isolated islets from HSL-deficient mice displayed elevated secretion at low (3 mmol/l) glucose, failed to release insulin in response to high (20 mmol/l) glucose, but had a normal secretion when challenged with elevated KCl. The phenotype of heterozygous mice with respect to the measured parameters in vitro was similar to that of wild type. Finally, the islet triglyceride content of HSL(-/-) mice was 2-2.5 fold that in HSL(-/+) and HSL(+/+) animals. The results demonstrate an important role of HSL and endogenous beta-cell lipolysis in the coupling mechanism of glucose-stimulated insulin secretion. The data also provide direct support for the concept that some lipid molecule(s), such as FFAs, fatty acyl-CoA or their derivatives, are implicated in beta-cell glucose signaling.
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PMID:A role for hormone-sensitive lipase in glucose-stimulated insulin secretion: a study in hormone-sensitive lipase-deficient mice. 1152 61


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