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PubMed1990

Inhibitory effect of tumor necrosis factor on gene expression of hormone sensitive lipase in 3T3-L1 adipocytes.

Recombinant human tumor necrosis factor (TNF) depressed the activities of both lipoprotein lipase (LPL) and hormone sensitive lipase (HSL) in 3T3-L1 adipocytes, 3 to 24 h after its introduction to the cells. HSL gene expression, as measured by Northern blotting analysis with 32P-labeled cloned HSL-cDNA, was also suppressed. These results suggested that the reduction in HSL activity caused by TNF resulted from inhibited gene expression of the enzyme.

Adipose Tissue↗
PubMed1999

Effect of diet on fat cell size and hormone-sensitive lipase activity.

This study was designed to examine the relationship between diet-induced insulin resistance/hyperinsulinemia, fat cell hypertrophy, and hormone-sensitive lipase (HSL) to elucidate whether an attenuated HSL activity leads to obesity. Female Fischer 344 rats were fed either a low-fat, complex-carbohydrate diet or a high-fat, refined-sugar (HFS) diet for 2 wk, 2 mo, or 6 mo. Adipose tissue morphology and HSL activity as well as plasma free fatty acid and glycerol levels were determined at these times. No differences between groups were seen after 2 wk except the previously reported hyperinsulinemia in the HFS animals. At both 2 and 6 mo, the HFS animals demonstrated adipocyte hypertrophy. Basal and stimulated HSL activities and plasma glycerol were significantly elevated in the HFS group. There was a positive correlation between adipocyte size and HSL activity for both basal and stimulated states. These results demonstrate that an attenuated HSL activity is not observed with the onset of insulin resistance/hyperinsulinemia and therefore does not play a role in the development of obesity.

Adipocytes↗
PubMed1996

Interferon and hormone sensitivity of endocrine-related tumors.

Interferons (IFNs) have been shown to enhance both in vitro and in vivo the antiproliferative activity of some hormones and anti-hormones which mainly act via steroid receptors. We discuss some of the mechanisms which could be involved in determining this effect in breast, endometrial and prostatic cancer cells, with a particular emphasis on steroid receptor modulation, reduction of the expression of epidermal growth factor receptors and, finally, down-regulation of some oncogenes. It seems that under appropriate conditions IFN might produce changes in cancer cells that enhance or restore hormone sensitivity. Nevertheless, available clinical data are too few to allow any conclusion to be drawn and this problem merits further investigations.

Androgens↗
PubMed1983

Arterial neutral cholesteryl esterase. A hormone-sensitive enzyme distinct from lysosomal cholesteryl esterase.

We describe here an activable neutral cholesteryl esterase (EC 3.1.1.13) in arteries similar to the hormone-sensitive lipase of adipose tissue and adrenal cortex. Maximum enzyme activity in rabbit aorta was given by cholesteryl ester substrates dispersed as a mixed micelle with phosphatidylcholine and Na taurocholate (molar ratio 1:4:2). A quantitative assay of enzymic activity was obtained with the following component concentrations: 6.0 microM cholesteryl [1-14C]oleate, 23.7 microM phosphatidylcholine, 12.5 microM Na taurocholate, 0.04% serum albumin, and 85 mM K phosphate buffer, pH 7.0. The enzymic activity in aortic homogenates was stimulated 2-fold by addition of 5 microM glucagon or 100 microM dibutyryl cAMP. This activation was Mg-ATP dependent. Addition of 50 micrograms/ml of exogenous protein kinase could reverse the action of protein kinase inhibitor on dibutyryl cAMP activation of the neutral cholesteryl esterase. In addition to activation by cAMP-dependent protein kinase, the enzyme could be distinguished from the more active arterial lysosomal cholesteryl esterase by its pH 7.0 optimum, relative stability to preincubation at elevated temperatures, and exclusive localization in the cell cytosol. Subcellular fractionation of lipid-laden arterial foam cells revealed a significant portion of the neutral cholesteryl esterase bound to cytoplasmic cholesteryl ester-rich lipid droplets. Our results suggest that the breakdown of cytoplasmic cholesteryl ester droplets in arterial cells may be under hormonal regulation.

Animals↗
PubMed1985

Chronic changes in male rats' hormone-sensitive systems after suprathreshold pulses of testosterone.

Adult male rats were castrated and maintained on daily SC injections of a threshold amount (200 micrograms) of testosterone propionate (TP). To mimic naturally occurring pulses of suprathreshold testicular hormones in intact males, animals in the experimental groups also received either one (single TP) or five (multiple TP) injections of 800 micrograms TP over 12 days. The rats were examined on the following day (acute) or 15 days later (chronic) for changes in hormone-sensitive behavior, physiology, and morphology. The hypothesis tested was that the hormonal pulses function to provoke chronic changes in substrates underlying the reproductive system. The results were that multiple doses of suprathreshold TP provoked acute modifications in aggressive behavior, sex accessory glands, and glans penis integrity. Chronic changes were observed in sex accessory gland functioning and penile morphology, particularly in the size of penile papillae. A single exposure to suprathreshold TP was considerably less effective, though there was some evidence of acute changes in sex accessory glands and chronic changes in penile papillae. There was substantial variation in the responses of individual animals, particularly the chronic responses. The data were interpreted as supporting the hypothesis.

Animals↗
PubMed1984

Partial purification from rat and pig liver of cytosolic stimulators of hormone-sensitive adenylate cyclase: quantitation and resolution of two components.

Procedures were carried out to isolate from liver cytosol the protein activators of hormone-sensitive adenylate cyclase. A method for quantifying amounts of activator protein was used to monitor recovery after each isolation step. The activator proteins were precipitable by ammonium sulfate (30-60% saturation) and partially recoverable from the precipitate. On gel filtration of cytosol, stimulatory activity for glucagon-sensitive adenylate cyclase was recovered in two peaks representing proteins with molecular weights of 49,000 and 25,500. Exposure to GTP-Sepharose reduced liver cytosol's content of stimulatory factors for glucagon-sensitive adenylate cyclase by up to 70%. However, soluble protein adenylate cyclase activators distinct from GTP could not be subsequently eluted from the affinity matrix. Purification efforts were thwarted by factor instability and large losses during simple and conventional steps despite the use of a variety of protein stabilizers and protease inhibitors. If the problem of stimulator instability can be overcome, large-scale purification should be possible using pig liver as a starting material.

Adenylyl Cyclases↗
PubMed2002

Hormone sensitive lipase expression and adipose tissue metabolism show gender difference in obese subjects after weight loss.

OBJECTIVE: The effect of weight reduction on hormone sensitive lipase (HSL) and lipoprotein lipase (LPL) gene expression and their relationship with adipose tissue metabolism were studied in massively obese men and women. SUBJECTS: Seventeen obese subjects (eight men, nine women) participated in the study (age 44+/-2 y, weight 145+/-8 kg, fat 40+/-2% of body mass, mean+/-s.e.m.), who were going through a gastric-banding operation for weight reduction. MEASUREMENTS: HSL and LPL mRNA expressions were analyzed using the reverse transcription competitive polymerase chain reaction. Subcutaneous fat lipolysis was measured in vivo by microdialysis and in vitro in isolated subcutaneous abdominal adipocytes. Measurements were done before and after 1 y of weight reduction. RESULTS: Significant reductions in weight (for men -20.3+/-2.5%, for women -18.3+/-2.1% (mean+/-s.e.m.) and fat mass (for men -27.6+/-7.9%, for women -21.8+/-3.9%) were observed in both genders. In women HSL mRNA expression decreased by 31% (P=0.008) and LPL expression increased slightly, but nonsignificantly (42%, P=0.110). These changes were not observed in men. In men, inhibition of lipolysis with alpha(2)-adrenergic and adenosine agonist was improved (P=0.001) in isolated adipocytes. CONCLUSIONS: This study uncovers new differences between genders in adipocyte metabolism along with weight reduction. In women, the observed changes in HSL and LPL gene expression suggest that deposition of lipids into adipose tissue might be favored after weight reduction. In men, the results indicate improved responsiveness to inhibition in adipose tissue metabolism along with weight reduction.

Adipocytes↗
PubMed1970

Hormone-sensitive adenyl cyclase: cytochemical localization in rat liver.

An electron microscopic procedure has been developed, using rat liver, for the localization of hormone-sensitive adenyl cyclase. Isoproterenol-sensitive adenyl cyclase is located almost exclusively in the parenchymal cells. In contrast, glucagon-sensitive adenyl cyclase is located primarily in the reticulo-endothelial cells but is also present in parenchymal cells. Sodium fluoride-sensitive adenyl cyclase is found in both cell types.

Adenine Nucleotides↗
PubMed2005

Human hormone-sensitive lipase (HSL): expression in white fat corrects the white adipose phenotype of HSL-deficient mice.

In white adipose tissue (WAT), hormone-sensitive lipase (HSL) can mediate lipolysis, a central pathway in obesity and diabetes. Gene-targeted HSL-deficient (HSL-/-) mice with no detectable HSL peptide or activity (measured as cholesteryl esterase) have WAT abnormalities, including low mass, marked heterogeneity of cell diameter, increased diacylglycerol content, and low beta-adrenergic stimulation of adipocyte lipolysis. Three transgenic mouse strains preferentially expressing human HSL in WAT were bred to a HSL-/- background. One, HSL-/- N, expresses normal human HSL (41.3 +/- 9.1% of normal activity); two express a serine-to-alanine mutant (S554A) initially hypothesized to be constitutively active: HSL-/- ML, 50.3 +/- 12.3% of normal, and HSL-/- MH, 69.8 +/- 15.8% of normal. In WAT, HSL-/- N mice resembled HSL+/+ controls in WAT mass, histology, diacylglyceride content, and lipolytic response to beta-adrenergic agents. In contrast, HSL-/- ML and HSL-/- MH mice resembled nontransgenic HSL-/- mice, except that diacylglycerol content and perirenal and inguinal WAT masses approached normal in HSL-/- MH mice. Therefore, 1) WAT expression of normal human HSL markedly improves HSL-/- WAT biochemically, physiologically, and morphologically; 2) similar levels of S554A HSL have a low physiological effect despite being active in vitro; and 3) diacylglycerol accumulation is not essential for the development of the characteristic WAT pathology of HSL-/- mice.

Adipocytes↗
PubMed1981

Hormone-sensitive adenylate cyclase in glomerular cells: possible role for inflammatory diseases of the glomerulus.

Using the adenylate cyclase assay after Ross we examined hormone sensitivity of isolated glomerular cells. cAMP production was increased 1.3--1.6-fold by stimulation with isoproterenol, 1.5--1.8 times by prostaglandin E1 and 1.4--1.5 times by histamine. The isoproterenol reaction could be completely inhibited by propranolol, the histamine effect was abolished by the H2-blocking agent cimetidine. As control we applied sodium fluoride, which directly activates the catalytic adenylate cyclase unit, increasing the activity 1.8--2.7 times (depending on the method of homogenization). These findings could reflect some physiological or pathophysiological implications, which are discussed in the present report.

Adenylyl Cyclases↗
PubMedDate not supplied

Monitoring of morphonuclear characteristics of hormone-sensitive and insensitive HCT-15 and LOVO human colorectal cells by means of digital cell image analysis.

We recently set up in vitro several human colorectal neoplastic cell lines that we labelled hormone-sensitive (HS) in comparison with the original cell lines which appeared to be rather "hormone-insensitive" (HI). We describe here the cell proliferation rate and the morphonuclear characteristics of the HS and HI variants of the HCT-15 and LOVO human neoplastic colorectal cell lines which were cultured either in serum-supplemented or chemically-defined media. Morphonuclear characteristics were monitored by means of the digital cell image analyses of Feulgen-stained nuclei, while the proliferation activity of the various cell types was assessed by means of the tetrazolium-based compound (MTT) assay. The results show that it is possible to culture human LOVO and HCT-15 colorectal cells in chemically defined media. This said, growth in a chemically defined medium is difficult for these cells and is markedly less sustained than when they are cultured in serum-supplemented media. The transition of the culture from a serum-supplemented medium to a chemically defined one is accompanied by a very marked drop in cell proliferation and a number of profound changes in terms of morphonuclear characteristics. These changes basically involve chromatin decondensation, which occurs as the result of the drop in the number of large chromatin clumps in the nucleus.

Cell Differentiation↗
PubMed2006

Muscle triacylglycerol and hormone-sensitive lipase activity in untrained and trained human muscles.

During exercise, triacylglycerol (TG) is recruited in skeletal muscles. We hypothesized that both muscle hormone-sensitive lipase (HSL) activity and TG recruitment would be higher in trained than in untrained subjects in response to prolonged exercise. Healthy male subjects (26 +/- 1 years, body moss index 23.3 +/- 0.5 kg m(-2)), either untrained (N = 8, VO(2max) 3.8 +/- 0.2 l min(-1)) or trained (N = 8, VO(2max) 5.1 +/- 0.1 l min(-1)), were studied. Before and after 3-h exercise (58 +/- 1% VO(2max)), a biopsy was taken. Muscle citrate synthase (32 +/- 2 vs. 47 +/- 6 mumol g(-1) min(-1) d.w.) and beta-hydroxy-acyl-CoA-dehydrogenase (38 +/- 3 vs. 52 +/- 5 mumol g(-1) min(-1) d.w.) activities were lower in untrained than in trained subjects (p < 0.05). Throughout the exercise, fat oxidation was higher in trained than in untrained subjects (p < 0.05). Muscle HSL activity was similar at rest (0.72 +/- 0.08 and 0.74 +/- 0.03 mU mg(-1) protein) and after exercise (0.71 +/- 0.1 and 0.68 +/- 0.03 mU mg(-1) protein) in untrained and trained subjects. At rest, the chemically determined muscle TG content (37 +/- 8 and 26 +/- 5 mmol g(-1) d.w.) was similar (p > 0.05), and after exercise it was unchanged in untrained and lower (p < 0.05) in trained subjects (41 +/- 9 and 10 +/- 2 mmol g((1) d.w.). Determined histochemically, TG was decreased (p < 0.05) after exercise in type I and II fibres. Depletion of TG was not different between fibre types in untrained, but tended to be higher (p = 0.07) in type I compared with type II fibres in trained muscles. In conclusion, HSL activity is similar in untrained and trained skeletal muscles both before and after prolonged exercise. However, the tendency to higher muscle TG recruitment during exercise in the trained subjects suggests a difference in the regulation of HSL or other lipases during exercise in trained compared with untrained subjects.

Adult↗
PubMed1994

Differences in hormone-sensitive lipase expression in white adipose tissue from various anatomic locations of the rat.

Regional differences in lipolytic activity of isolated fat cells have been observed in rats, with internal fat depots displaying greater rates of lipolysis than subcutaneous fat. These differences in lipolysis have been attributed to a variety of mechanisms, including regional differences in adrenergic receptors, in adenosine sensitivity, and in regional blood flow. In the present study, we have explored whether differences in hormone-sensitive lipase (HSL), the rate-limiting enzyme in lipolysis, might contribute to regional differences in lipolysis in the rat. Adipocytes were isolated from epididymal, retroperitoneal, and dorsal-subcutaneous fat depots, and HSL activity, HSL immunoreactive protein, the rate of HSL synthesis, and the steady-state levels of HSL mRNA were assessed. HSL activity was similar in epididymal and retroperitoneal adipocytes, but was twofold to 2.5-fold greater in these cells than in subcutaneous adipocytes (P < .01). The amount of immunoreactive HSL protein was also similar in epididymal and retroperitoneal adipocytes, but was twofold greater in these cells than in subcutaneous adipocytes (P < .001). The rate of incorporation of 35S-methionine into immunoprecipitable HSL was approximately 2.5-fold greater in epididymal than in subcutaneous adipocytes (P < .01). Finally, HSL mRNA levels were similar in epididymal and retroperitoneal fat depots, and were approximately 1.4-fold greater in these cells than in subcutaneous adipocytes (P < .001). These results demonstrate that site-related differences in the rate of basal lipolysis among various fat depots in the rat are in part due to variations in the expression of HSL.

Adipose Tissue↗
PubMed2002

The hormone-sensitive lipase gene and body composition: the HERITAGE Family Study.

OBJECTIVE: To investigate whether the C-60G polymorphism and other markers in the hormone-sensitive lipase (LIPE) gene are associated with baseline body composition and free-fatty acid (FFA) concentrations measured at rest and during low-intensity exercise in white and black subjects participating in the HERITAGE Family Study. SUBJECTS: Adult sedentary white (245 men and 258 women) and black (91 men and 185 women) subjects. MEASUREMENTS: body mass index (BMI); fat mass (FAT); percentage body fat (%FAT); fat-free mass (FATFR); sum of eight skinfolds (SF8); subcutaneous (ASF), visceral (AVF) and total (ATF) abdominal fat areas assessed by CT scan; plasma FFA concentrations measured at rest (FFAR), at a power output of 50 W (FFA50) and at a relative power output of 60% of VO(2max) (FFA60%); and fasting insulin (INS). STATISTICAL ANALYSIS: Association between the C-60G polymorphism of the LIPE gene and each phenotype was tested separately in men and women using ANCOVA with the effects of age and race as covariates and with further adjustment for FAT for ASF, AVF, ATF, FFAR, FFA50 and FFA60%. Secondly, owing to significant gene-by-race interaction, associations were investigated separately in each of the two race groups. Linkage was tested with the C-60G polymorphism, a dinucleotide repeat polymorphism in the intron 7 of the LIPE gene and two microsatellites markers (D19S178 and D19S903) flanking the LIPE gene. RESULTS: There were no race differences in the allele frequencies of the C-60G polymorphism of the LIPE gene. No association or gene-by-race interaction was observed in men. However, in women, strong gene-by-race interactions were observed for BMI (P=0.0005), FAT (P=0.0007), %FAT (P=0.0003), SF8 (P=0.0001), ASF (P=0.03) and ATF (P=0.01). When the analysis was performed separately in each race, white women carriers of the -60G allele exhibited lower %FAT (P=0.005) and SF8 (P=0.01) than non-carriers, while in black women, the -60G allele was associated with higher BMI (P=0.004), FAT (P=0.009), %FAT (P=0.01) and SF8 (P=0.0009). These associations were no longer significant after adjusting for INS. Evidence of linkage was observed in whites with ATF, FFAR, FFA50 and FFA60%. CONCLUSION: These results suggest that the C-60G polymorphism in the LIPE gene plays a role in determining body composition and that its effect is sex-, race- and insulin-dependent.

Abdomen↗
PubMed1983

Hormonal activation of type-L hormone-sensitive lipase measured in defatted heart powders.

Adrenaline, 3-isobutyl-1-methylxanthine (MIX) and dibutyryl cyclic AMP (Bt2 cyclic AMP) stimulated type-L hormone-sensitive lipase (HSL) activity when measurements were made on defatted rat heart powders. These lipolytic agents stimulated the activity of this enzyme in a time- and dose-dependent manner. This activation was reversible, because removal of adrenaline from the perfusate was accompanied by the return of type-L HSL activity to control levels. We have reported [Palmer, Caruso & Oscai (1981) Biochem. J. 198, 159-166] that perfusion with low levels of adrenaline, MIX or Bt2 cyclic AMP reduced type-L HSL activity below control levels when measurements were made in aqueous homogenates. However, in the present study, when activities were measured in acetone/diethyl ether heart powders, all concentrations of these agents studied stimulated enzyme activity, and at no concentration was there enzyme inhibition. These data suggest that acetone/diethyl ether treatment may remove a factor that plays a role in type-L HSL regulation. Type-L HSL activity measured in acetone/diethyl ether powders of control and stimulated rat heart exhibited properties that include alkaline pH optimum, serum requirement, activation by heparin and inhibition by high salt and protamine sulphate. These characteristics, in addition to the stability of the enzyme to treatment with organic solvents, fulfil the requirements for the type-L HSL classification.

1-Methyl-3-isobutylxanthine↗
PubMed2003

Fatty acid-binding protein-hormone-sensitive lipase interaction. Fatty acid dependence on binding.

Adipose lipolysis is mediated, in part, via interaction of fatty acid-binding protein (FABP) with hormone-sensitive lipase (HSL). Mice with reduced FABP content in fat (adipocyte FABP null) exhibit diminished fat cell lipolysis, whereas transgenic mice with increased FABP content in fat (epithelial FABP transgenic) exhibit enhanced lipolysis. To examine the relationship between the binding of FABP to HSL and activation of catalytic activity, isothermal titration microcalorimetry as well as kinetic analysis using a variety of FABP isoforms have been employed. In the absence of fatty acids, no FABP-HSL association could be demonstrated for any FABP form. However, in the presence of 10 microm oleate, A-FABP and E-FABP each bound to HSL with high affinity (Kd of 0.5 and 3 nM, respectively) in a approximately 1:1 molar stoichiometry, whereas liver FABP and intestinal FABP did not exhibit any association. To compare binding to catalysis, each FABP isoform was incubated with HSL in vitro, and enzymatic activity was assessed. Importantly, each FABP form stimulated HSL activity approximately 2-fold using cholesteryl oleate as substrate but exhibited no activation using p-nitrophenyl butyrate. The activation by A-FABP was dependent upon its fatty acid binding properties because a non-fatty acid binding mutant, R126Q, failed to activate HSL. These results suggest that binding and activation of HSL by FABPs are separate and distinct functions and that HSL contains a site for fatty acid binding that allows for FABP association.

Anilino Naphthalenesulfonates↗
PubMed2004

Hormone-sensitive lipase-independent adipocyte lipolysis during beta-adrenergic stimulation, fasting, and dietary fat loading.

In white adipose tissue, lipolysis can occur by hormone-sensitive lipase (HSL)-dependent or HSL-independent pathways. To study HSL-independent lipolysis, we placed HSL-deficient mice in conditions of increased fatty acid flux: beta-adrenergic stimulation, fasting, and dietary fat loading. Intraperitoneal administration of the beta(3)-adrenergic agonist CL-316243 caused a greater increase in nonesterified fatty acid level in controls (0.33 +/- 0.05 mmol/l) than in HSL(-/-) mice (0.12 +/- 0.01 mmol/l, P < 0.01). Similarly, in isolated adipocytes, lipolytic response to CL-316243 was greatly reduced in HSL(-/-) mice compared with controls. Fasting for <or=48 h produced normal mobilization and oxidation of fatty acids in HSL(-/-) mice, as judged by similar values of respiratory quotient and oxygen consumption as in HSL(+/+) controls. In isolated adipocytes, lipolysis in the absence of beta-adrenergic stimulation was 1.9-fold greater in HSL(-/-) than in HSL(+/+) cells (P < 0.05), increasing to 6.5-fold after fasting (P < 0.01). After 6 wk of a fat-rich diet containing 31.5% of energy as lipid, weight gain of HSL(-/-) mice was 4.4-fold less than in HSL(+/+) mice (P < 0.01), and total abdominal fat mass was 5.2-fold lower in HSL(-/-) than in HSL(+/+) mice (P < 0.01). In white adipose tissue, HSL is essential for normal acute beta-adrenergic-stimulated lipolysis and permits normal triglyceride storage capacity in response to dietary fat loading. However, HSL-independent lipolysis can markedly increase during fasting, both in isolated adipocytes and in intact mice, and can mediate a normal flux of fatty acids during fasting.

Adipocytes↗