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PubMed1980

Dissociation of the lipid-enzyme complex of hormone-sensitive lipase using high density lipoprotein or apolipoprotein A-I.

Hormone-sensitive lipase in homogenates of adipose tissue occurs as a large, lipid-rich complex including several acylhydrolase activities that emerge quantitatively in the void volume on gel filtration chromatography (2% agarose). Incubation with intact human plasma high density lipoprotein or with lipid-free apolipoprotein A-I, however, disrupted the lipid-rich complex almost completely and most of the enzyme activity eluted from a 2% agarose column at about Ve = 2.3 x Vo. This use of the detergent-like properties of apolipoprotein A-I may be of value for dissociation of other lipid-associated or membrane-bound enzymes.

Adipose Tissue↗
PubMed2004

Might the kinetic behavior of hormone-sensitive lipase reflect the absence of the lid domain?

Hormone-sensitive lipase (HSL) is thought to contribute importantly to the mobilization of fatty acids from the triacylglycerols (TAGs) stored in adipocytes, providing the main source of energy in mammals. To investigate the HSL substrate specificity more closely, we systematically assessed the lipolytic activity of recombinant human HSL on solutions and emulsions of various vinyl esters and TAG substrates, using the pH-stat assay technique. Recombinant human HSL activity on solutions of partly soluble vinyl esters or TAG was found to range from 35 to 90% of the maximum activity measured with the same substrates in the emulsified state. The possible existence of a lipid-water interface due to the formation of small aggregates of vinyl esters or TAG in solution may account for the HSL activity observed below the solubility limit of the substrate. Recombinant human HSL also hydrolyzes insoluble medium- and long-chain acylglycerols such as trioctanoylglycerol, dioleoylglycerol, and olive oil, and can therefore be classified as a true lipase. Preincubation of the recombinant HSL with a serine esterase inhibitor such as diethyl p-nitrophenyl phosphate in 1:100 molar excess leads to complete HSL inhibition within 15 min. This result indicates that the catalytic serine of HSL is highly reactive and that it is readily accessible. Similar behavior was also observed with lipases with no lid domain covering their active site, or with a deletion in the lid domain. The 3-D structure of HSL, which still remains to be determined, may therefore lack the lid domain known to exist in various other lipases.

Electrophoresis, Polyacrylamide Gel↗
PubMed2004

Synthesis and structure-activity relationship for a novel class of potent and selective carbamoyl-triazole based inhibitors of hormone sensitive lipase.

The central role of the intracellular enzyme hormone-sensitive lipase (HSL) in regulating fatty acid metabolism makes it an interesting pharmacological target for the treatment of insulin resistant and dyslipidemic disorders where a decrease in delivery of fatty acids to the circulation is desirable, e.g., in individuals with type 2 diabetes, metabolic syndrome, or impaired glucose tolerance. On the basis of a lead structure from high throughput screening, we have identified a very potent type of carbamoyl-triazole inhibitors of HSL. As part of the lead optimization program, four new classes of carbamoyl-triazoles were synthesized and tested with respect to potency, efficacy and selectivity. Methyl-phenyl-carbamoyl-triazoles were identified as potent and efficacious HSL inhibitors. These compounds do not inhibit other hydrolases such as hepatic lipase, lipoprotein lipase, pancreatic lipase, and butyrylcholine esterase. However, the inhibitors 4b and 4g with IC(50) values for HSL of 0.17 and 0.25 microM, respectively, were the only inhibitors selective against acetylcholine esterase. A reversible pseudosubstrate inhibition mechanism is proposed for this class of inhibitors.

Binding Sites↗
PubMed2001

Stimulation of lipolysis and hormone-sensitive lipase via the extracellular signal-regulated kinase pathway.

Hormonally stimulated lipolysis occurs by activation of cyclic AMP-dependent protein kinase (PKA) which phosphorylates hormone-sensitive lipase (HSL) and increases adipocyte lipolysis. Evidence suggests that catecholamines not only can activate PKA, but also the mitogen-activated protein kinase pathway and extracellular signal-regulated kinase (ERK). We now demonstrate that two different inhibitors of MEK, the upstream activator of ERK, block catecholamine- and beta(3)-stimulated lipolysis by approximately 30%. Furthermore, treatment of adipocytes with dioctanoylglycerol, which activates ERK, increases lipolysis, although MEK inhibitors decrease dioctanoylglycerol-stimulated activation of lipolysis. Using a tamoxifen regulatable Raf system expressed in 3T3-L1 preadipocytes, exposure to tamoxifen causes a 14-fold activation of ERK within 15-30 min and results in approximately 2-fold increase in HSL activity. In addition, when differentiated 3T3-L1 cells expressing the regulatable Raf were exposed to tamoxifen, a 2-fold increase in lipolysis is observed. HSL is a substrate of activated ERK and site-directed mutagenesis of putative ERK consensus phosphorylation sites in HSL identified Ser(600) as the site phosphorylated by active ERK. When S600A HSL was expressed in 3T3-L1 cells expressing the regulatable Raf, tamoxifen treatment fails to increase its activity. Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL.

3T3 Cells↗
PubMed2003

A novel hormone-sensitive lipase isoform expressed in pancreatic beta-cells.

Hormone-sensitive lipase (HSL) is a key enzyme in fatty acid mobilization in many cell types. Two isoforms of HSL are known to date, namely HSL(adi) (84 kDa in rat) and HSL(tes) (130 kDa in rat). These are encoded by the same gene, with exons 1-9 encoding the parts that are common to both and an additional 5'-exon encoding the additional amino acids in HSL(tes). HSL of various tissues, among these the islet of Langerhans, is larger than HSL(adi), but not as large as HSL(tes), indicating that there may be other 5'-coding exons. Here we describe the molecular basis for a novel 89-kDa HSL isoform that is expressed in beta-cells, adipocytes, adrenal glands, and ovaries in the rat and that is encoded by exons 1-9 and exon A, which is spliced to exon 1 and thereby introducing an upstream start codon. The additional 5'-base pairs encode a 43-amino acid peptide, which is highly positively charged. Conglomerates of HSL molecules are in close association with the secretory granules of the beta-cell, as determined by immunoelectron microscopy with antibodies targeting two separate regions of HSL. We have also determined that the human genomic sequence upstream of exon A has promoter activity in INS-1 cells as well as glucose sensing capability, mediating an increase in expression at high glucose concentration. The minimal promoter is present within 170 bp from the transcriptional start site and maximal glucose responsiveness is conferred by sequence within 850 bp from the transcriptional start site.

Adipocytes↗
PubMed1998

The metabolism of 3-phenoxybenzoic acid-containing xenobiotic triacylglycerols in vitro by pancreatic, hormone-sensitive and lipoprotein lipases.

Two model substrates, rac-1-(3-phenoxy-[ring-14C]benzoyl)-2,3-dipalmitoyl glycerol (1(3PBA)DPG) and sn-2-(3-phenoxy-[ring-14C]benzoyl)-1,3-dipalmitoyl glycerol (2(3PBA)DPG), were compared with tri[1-14C]palmitoylglycerol or tri[9,10(n)-3H]oleoylglycerol as substrates for pancreatic lipase, lipoprotein lipase, and hormone-sensitive lipase. The loss of 3PBA from the sn-2 position was always low because of the positional specificity of the lipases. The loss of 3PBA from the rac-1 position was similarly low with hormone-sensitive lipase (about 7% of the loss of oleate), but higher with pancreatic lipase (about 35% that of oleate) and lipoprotein lipase (about 23% that of oleate). With one exception, more than 50% and up to 80% of the 14C-3PBA was still in the form of a diacylglycerol after incubation with a lipase, whereas free acid or monoacylglycerol forms would have been expected. Lipoprotein lipase acting on 1-(14C-3PBA)DPG produced nearly 70% of its product as nonesterified 3PBA and only 25% as the diacylglycerol. The results suggest that 3PBA-containing xenobiotic triacylglycerols, and the 3PBA-glycerol ester bond in particular, are poorer substrates for lipases than are their natural counterparts, with the result that high proportions of partially digested xenobiotic acylglycerols are produced. The three lipases performed differently with the xenobiotic substrates; this could have consequences for the relative rates of storage and clearance of the xenobiotic triacylglycerols from the body.

Animals↗
PubMed1994

Hormone-sensitive lipase is closely related to several bacterial proteins, and distantly related to acetylcholinesterase and lipoprotein lipase: identification of a superfamily of esterases and lipases.

We have sequenced a gene from Bacillus acidocaldarius which encodes an open reading frame (ORF3) of 310 amino acids. The ORF3 was found to be related to the mammalian hormone-sensitive lipase (HSL). Searching the protein data base revealed five other bacterial proteins related to the HSL. Upon further sequence comparisons this HSL-group was found to be related to the family of carboxylesterases, and to a family of lipases (lipoprotein, hepatic and pancreatic lipases). The evolutionary relationship of these serine-dependent hydrolytic enzymes has not been studied previously, and it has not been known that these proteins belong to the same superfamily. Finally, the alignment of the HSL with the bacterial proteins allowed us to infer the location of the hormone-sensitive regulatory domain of the HSL-protein.

Acetylcholinesterase↗
PubMed1986

Demonstration of the amphiphilic character of hormone-sensitive lipase by temperature-induced phase separation in Triton X-114 and charge-shift electrophoresis.

Temperature-induced phase separation in Triton X-114 (Bordier, C. (1981) J. Biol. Chem. 256, 1604-1607) and charge-shift electrophoresis (Helenius, A., and Simons, K. (1977) Proc. Natl. Acad. Sci. U. S. A. 74, 529-532) were used to examine the amphiphilic character of hormone-sensitive lipase, purified from rat adipose tissue. In contrast to ATP-citrate lyase, a reference hydrophilic protein, the lipase was shown to partition predominantly (approximately 80%) into the detergent-rich phase upon phase separation in Triton X-114. Furthermore, its electrophoretic mobility was markedly shifted anodally and cathodally upon charge-shift electrophoresis in the presence of sodium taurodeoxycholate and cetyltrimethylammonium bromide, respectively. The results demonstrate that hormone-sensitive lipase possesses detergent-binding hydrophobic domain(s) and exhibits the same amphiphilicity as typical intrinsic membrane proteins.

ATP Citrate (pro-S)-Lyase↗
PubMed2003

Regulation of Bcl-2 expression by dihydrotestosterone in hormone sensitive LNCaP-FGC prostate cancer cells.

PURPOSE: Up-regulation of the anti-apoptotic bcl-2 proto-oncogene is associated with androgen independent prostate cancer progression. This observation suggests that the expression of bcl-2 may be negatively regulated by androgens in prostate cancer cells. MATERIALS AND METHODS: The expression of the proto-oncogene bcl-2 was assessed in the hormone sensitive prostate cancer cell line LNCaP-FGC in the presence and absence of a physiological concentration of 1 nM. dihydrotestosterone (DHT). Sequence analysis of the bcl-2 promoter regions demonstrated the presence of 2 potential androgen response elements. Transient transfections of luciferase reporter constructs containing these potential androgen response elements into LNCaP-FGC cells in the presence and absence of DHT were performed. Steady-state transcripts of bcl-2 were assessed using RNase protection assays. RESULTS: Cells cultured in charcoal stripped serum in the presence of DHT resulted in down-regulation of bcl-2 protein. Down-regulation of bcl-2 protein and mRNA by DHT was inhibited by coincubation with the antiandrogen bicalutamide, an agent that competitively inhibits binding of DHT to androgen receptor. Luciferase reporter constructs containing candidate androgen response elements were transrepressed in the presence of DHT. Bcl-2 mRNA was also down-regulated by DHT and this down-regulation could not be abolished by cycloheximide. CONCLUSIONS: Together these results suggest that the suppression of bcl-2 expression by DHT in hormone sensitive LNCaP-FGC prostate cancer cells occurs directly. In addition, these results provide a possible mechanistic basis for the up-regulation (derepression) of bcl-2 observed in hormone independent prostate cancers.

Dihydrotestosterone↗
PubMed1994

Hormonal regulation of hormone-sensitive lipase activity and mRNA levels in isolated rat adipocytes.

Hormone-sensitive lipase (HSL) mediates the lipolysis of triacylglycerol from mammalian adipocytes, resulting in the release of non-esterified fatty acids and glycerol. Although numerous studies have examined the hormonal regulation of HSL, the measurement of HSL mRNA levels in response to hormonal regulators has not been studied. This study was designed to determine the effects of epinephrine, growth hormone, glucagon, and dexamethasone on HSL expression by measuring HSL mRNA levels and glycerol release in primary cultures of rat adipocytes. Exposure of adipocytes to epinephrine at 10(-7) M and 10(-5) M for 4 h resulted in an increase in medium glycerol (209 +/- 46%, and 284 +/- 58% of control, P < 0.001, respectively). However, no change in HSL mRNA levels occurred due to the epinephrine treatment. Similarly, the peptides glucagon (10(-7) M and 10(-5) M for 4 h) and growth hormone (100 ng/ml for 24 h) resulted in increased medium glycerol and had no effect on HSL mRNA levels in adipocytes. Dexamethasone was added to adipocyte cultures for 4 and 24 h, and resulted in a dose-dependent increase of medium glycerol (102 +/- 8%, 138 +/- 8% (P < 0.001), and 168 +/- 24% (P < 0.001) for 10(-8) M, 10(-7) M, and 10(-6) M, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1988

Charge heterogeneity of human mammary tumor estrogen receptors. Relationship with a hormonal sensitivity tumor marker.

A high resolution quantitative method for estrogen receptor analysis has been elaborated using isoelectric focusing in 0.5% agarose gel, without any prior trypsin digestion. The 23 cytosols analyzed were stabilized by molybdate and prepared from human mammary tumors with progesterone receptors (PR + cytosols) or without (PR - cytosols). Progesterone receptor was used as a tumoral hormonal sensitivity marker. The estrogen receptors usually resolved as 4 isoform peaks of close isoelectric points. In PR - cytosols, the mean pI values were 4.7, 5.5, 6 and 6.5. Significant differences between the two cytosol populations were observed concerning pI 4.7 and 6.5 isoforms. In PR - cytosols, the pI 4.7 isoform occurred in greater proportions than in PR + cytosols, whereas lower proportions of pI 6.5 isoform were seen. The comparison between high performance size exclusion chromatography profiles and isoelectric focusing patterns, before and after cytosol incubation at 28 degrees C with KCl (0.4 M), confirmed an oligomer structure for the pI 4.7 isoform and suggested a monomer structure (Stokes radius 2.9 mm) for the pI 6.5 estrogen receptor isoform. The results indicated that isoelectric focusing analysis of estrogen receptors could be useful in the prediction of breast cancer hormonal sensitivity.

Aged↗
PubMed2002

Lipolysis in the absence of hormone-sensitive lipase: evidence for a common mechanism regulating distinct lipases.

Hormone-sensitive lipase (HSL) is presumed to be essential for lipolysis, which is defined as the mobilization of free fatty acids from adipocytes. In the present study, we investigated the effects of various lipolytic hormones on the lipolysis in adipocytes derived from mouse embryonic fibroblasts (MEF adipocytes) prepared from HSL-deficient mice (HSL-/-). HSL-/- MEF differentiated into mature adipocytes in a manner indistinguishable from that of wild-type mice. Both isoproterenol (ISO) and tumor necrosis factor (TNF)-alpha stimulated the rate of lipolysis in HSL-/- MEF adipocytes, although to a lesser extent than in wild-type cells, and these lipolytic activities were inhibited by H-89, a cAMP-dependent protein kinase inhibitor, and troglitazone, respectively. Thus, the responses of the residual lipolytic activity to lipolytic hormones and TNF-alpha were well conserved in the absence of HSL. Extracts from HSL-/- MEF adipocytes hydrolyzed triacylglycerol (TG) but not cholesterol ester, indicating that the residual lipolytic activity was mediated by another TG-specific lipase. The TG lipase activity, which was decreased in cytosolic fraction in response to ISO, was increased in fat cake fraction. Therefore, translocation of the TG lipase may explain, at least partially, the ISO-stimulated lipolysis in HSL-/- adipocytes. In conclusion, lipolysis is mediated not only by HSL but also by the non-HSL TG lipase, whose responses to lipolytic hormones are similar to those of HSL. We propose that both lipases are regulated by common mechanism of lipolysis.

Adipocytes↗
PubMed2004

Normal and pathological human testes express hormone-sensitive lipase and the lipid receptors CLA-1/SR-BI and CD36.

Numerous studies have demonstrated the important role of cholesterol and cholesteryl esters in tumor cell proliferation and progression of cancer. However, few studies have focused on the role of lipid transporters and lipases in cancer development and progression. The present study examined the expression of hormone-sensitive lipase (HSL) and the scavenger receptors CLA-1/SR-BI and CD36 in normal human testis and in nontumor and tumor testicular disorders by immunohistochemistry and Western blotting analysis. In normal young testes, immunoreaction to CLA-1/SR-BI was found in the spermatid acrosomic vesicle and on the surface of Sertoli and Leydig cells. HSL was detected in spermatogonia, the Golgi region of spermatocytes, the nucleus of spermatids, and the cytoplasm of both Sertoli and Leydig cells. Elderly testes and testes with hypospermatogenesis showed a similar staining pattern to that of normal young testes except for CD36, which was expressed in Sertoli cells. Cryptorchid testes demonstrated intense labeling to HSL and weak labeling to SR-BI in Sertoli cells (nucleus and cytoplasm) and Leydig cells (cytoplasm). Seminiferous tubules with intratubular germ cell neoplasia exhibited intense immunolabeling to the 3 lipid receptors in the surface of neoplastic cells and to HSL in the nucleus. In seminoma and spermatocytic seminoma, neoplastic cells labeled to HSL but failed to stain with antilipid receptors; in the seminiferous tubules at the periphery of the tumour, Charcot-Böttcher crystalloids of Sertoli cells were strongly positive to CLA-1. Testes with mature teratoma showed a weak reaction to CD36 and SR-BI in some cells of enteric-type glands, and immature teratoma were exclusively immunolabeled with HSL. Western blotting analysis revealed that multiple bands were immunolabeled, with differences seen between normal and pathological testes. The results of this study indicate that the presence of lipid receptors (CLA-1/SR-BI) and hormone-sensitive lipase in Leydig cells suggests a role of these proteins in steroidogenesis. Also, these proteins seem to be involved in spermiogenesis, as their labeling in spermatids suggests. In nonmalignant and malignant pathologies, cholesterol metabolism is probably altered, and HSL labeling in neoplastic germ cell nuclei suggests a still-unknown function of this enzyme, probably related to cell cycle regulation.

Adult↗
PubMed1999

Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages.

Foam cells formed from receptor-mediated uptake of lipoprotein cholesterol by macrophages in the arterial intima are critical in the initiation, progression, and stability of atherosclerotic lesions. Macrophages accumulate cholesterol when conditions favor esterification by acyl-CoA:cholesterol acyltransferase (ACAT) over cholesteryl-ester hydrolysis by a neutral cholesteryl-ester hydrolase, such as hormone-sensitive lipase (HSL), and subsequent cholesterol efflux mediated by extracellular acceptors. We recently made stable transfectants of a murine macrophage cell line, RAW 264.7, that overexpressed a rat HSL cDNA and had a 5-fold higher rate of cholesteryl-ester hydrolysis than control cells. The current study examined the effect of macrophage-specific HSL overexpression on susceptibility to diet-induced atherosclerosis in mice. A transgenic line overexpressing the rat HSL cDNA regulated with a macrophage-specific scavenger receptor promoter-enhancer was established by breeding with C57BL/6J mice. Transgenic peritoneal macrophages exhibited macrophage-specific 7-fold overexpression of HSL cholesterol esterase activity. Total plasma cholesterol levels in transgenic mice fed a chow diet were modestly elevated 16% compared to control littermates. After 14 weeks on a high-fat, high-cholesterol diet, total cholesterol increased 3-fold, with no difference between transgenics and controls. However, HSL overexpression resulted in thicker aortic fatty lesions that were 2.5-times larger in transgenic mice. HSL expression in the aortic lesions was shown by immunocytochemistry. Atherosclerosis was more advanced in transgenic mice exhibiting raised lesions involving the aortic wall, along with lipid accumulation in coronary arteries occurring only in transgenics. Thus, increasing cholesteryl-ester hydrolysis, without concomitantly decreasing ACAT activity or increasing cholesterol efflux, is not sufficient to protect against atherosclerosis. hormone-sensitive lipase overexpression in macrophages.

Animals↗
PubMed1997

Hormone-sensitive seizures in women with epilepsy.

Until the associations between seizures and hormones are better understood, finding appropriate therapies for hormone-sensitive seizures remains problematic. Most importantly, women with epilepsy need information about the complex interactions of brain function, hormones, seizures, and medications. Nurses can educate women concerning the hormonal aspects of epilepsy and methods of assessing seizures in relation to menstrual patterns. Nurses can also serve as patient advocates, ensuring that their patients are heard, and that they have access to appropriate care and are informed about therapeutic options that can improve seizure control and quality of life.

Adult↗
PubMed1992

Evidence for two distinct hormone-sensitive [3H]phosphoinositide pools in bovine adrenocortical zona fasciculata/reticularis cells stimulated with angiotensin II.

Bovine adrenocortical cells from the zona fasciculata/reticularis were isolated and their phosphoinositides labelled to a steady state with [3H]inositol in primary culture. Experiments performed on these cells in the presence of Li+ have shown that, over a period of 60 min, angiotensin II (AII; 10(-7) M) stimulated a linear increase in [3H]inositol phosphates that was sustained through the utilization of two hormone-sensitive subpools of prelabelled lipid (30% and 45% respectively), and a rapid resynthesis of [3H]phosphoinositide into one of these pools using cytosolic [3H]inositol. The 30% pool was used immediately on stimulation, and was sustained at a steady-state size of 10-15% during the first 30 min of stimulation through rapid resynthesis using cytosolic [3H]inositol. Only after 30 min, when the cytosolic [3H]inositol was depleted and resynthesis could no longer occur, did the additional 45% pool start to supply further substrate to the phospholipase C, thereby further sustaining the generation of [3H]inositol phosphates. Once this pool was depleted however (by approximately 60 min), [3H]inositol phosphate generation finally ceased. These findings establish the differential use of two metabolically distinct hormone-sensitive pools of phosphoinositide following AII stimulation in bovine adrenocortical cells, events which are dependent upon the availability of cytosolic inositol for phosphoinositide resynthesis.

Angiotensin II↗
PubMed1986

Phosphorylation of the basal site of hormone-sensitive lipase by glycogen synthase kinase-4.

In rat adipocytes hormone-sensitive lipase is phosphorylated at two sites termed 'regulatory' and 'basal', in the former case by cyclic AMP-dependent protein kinase causing an activation of the lipase [(1984) Proc. Natl. Acad. Sci. USA 81, 3317-3321]. Here, the basal phosphorylation site was found to be phosphorylated by glycogen synthase kinase-4 without any effects on lipase activity, or on the extent of its activation subsequent to phosphorylation of the regulatory site. Glycogen synthase kinase-3, casein kinase-I, and casein kinase-II did not phosphorylate the lipase. Phosphorylase kinase phosphorylated it to a very low extent at a third phosphorylation site not phosphorylated in the fat cell.

Adipose Tissue↗
PubMed1979

Hormone sensitivity of gynecological tumor cells in tissue culture.

Proliferating tumor cells obtained from ovarian, mammary, and endometrial tumors in tissue culture were tested for the influence of proteohormones and steroid hormones on cellular DNA synthesis and cell growth. The gonadotropic hormones stimulated DNA synthesis of ovarian tumor cells by single administration, or in combination with cortisol, up to the 11-fold of the comparable controls. The hormone sensitivity of the cell lines was variable, resulting in individual reaction patterns. There was no correlation to the histological diagnosis of the primary tumors with respect to the grade of differentiation. The results suggest that ovarian tumor cells in tissue culture can maintain sensitivity to organotropic hormones. Compared to the ovarian carcinoma lines, mammary or endometrial tumor cells did not respond to a similar extent. Progesterone decreased DNA synthesis of endometrial carcinoma cells.

Breast Neoplasms↗