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PubMed2006

Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms.

Hormone-sensitive lipase (HSL) is the predominant lipase effector of catecholamine-stimulated lipolysis in adipocytes. HSL-dependent lipolysis in response to catecholamines is mediated by protein kinase A (PKA)-dependent phosphorylation of perilipin A (Peri A), an essential lipid droplet (LD)-associated protein. It is believed that perilipin phosphorylation is essential for the translocation of HSL from the cytosol to the LD, a key event in stimulated lipolysis. Using adipocytes retrovirally engineered from murine embryonic fibroblasts of perilipin null mice (Peri-/- MEF), we demonstrate by cell fractionation and confocal microscopy that up to 50% of cellular HSL is LD-associated in the basal state and that PKA-stimulated HSL translocation is fully supported by adenoviral expression of a mutant perilipin lacking all six PKA sites (Peri Adelta1-6). PKA-stimulated HSL translocation was confirmed in differentiated brown adipocytes from perilipin null mice expressing an adipose-specific Peri Adelta1-6 transgene. Thus, PKA-induced HSL translocation was independent of perilipin phosphorylation. However, Peri Adelta1-6 failed to enhance PKA-stimulated lipolysis in either MEF adipocytes or differentiated brown adipocytes. Thus, the lipolytic action(s) of HSL at the LD surface requires PKA-dependent perilipin phosphorylation. In Peri-/- MEF adipocytes, PKA activation significantly enhanced the amount of HSL that could be cross-linked to and co-immunoprecipitated with ectopic Peri A. Notably, this enhanced cross-linking was blunted in Peri-/- MEF adipocytes expressing Peri Adelta1-6. This suggests that PKA-dependent perilipin phosphorylation facilitates (either direct or indirect) perilipin interaction with LD-associated HSL. These results redefine and expand our understanding of how perilipin regulates HSL-mediated lipolysis in adipocytes.

Adipocytes↗
PubMed2003

Decreased fatty acid esterification compensates for the reduced lipolytic activity in hormone-sensitive lipase-deficient white adipose tissue.

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.

Acyltransferases↗
PubMed1972

Rapid assay for hormone-sensitive lipase activity of adipose tissue.

A highly specific and rapid assay for hormone-sensitive lipase activity of rat adipose tissue is described. The method employs emulsified 2,3-di-O-oleyl-[9,10-(3)H(2)]oleoyl glycerol as a substrate; it is very sensitive and is suitable for serial sampling.

Adenosine Triphosphate↗
PubMed1997

Overexpression of hormone-sensitive lipase in Chinese hamster ovary cells leads to abnormalities in cholesterol homeostasis.

Hormone-sensitive lipase (HSL) is an intracellular enzyme that functions as both a neutral triglyceride and cholesteryl ester hydrolase. In order to explore the effects of HSL on cholesterol homeostasis, Chinese hamster ovary (CHO) cells were transfected with rat HSL and several different stable cell lines that overexpress HSL mRNA, HSL protein, and HSL activity approximately 600-fold were isolated. Cells transfected with HSL contained less cholesteryl esters and unesterified cholesterol than control cells. HSL transfectants expressed 20-60% fewer LDL receptors than control cells when grown in lipid-depleted media or in the presence of mevinolin, as assessed by binding and degradation of LDL and immunoblotting of LDL receptors. In contrast, the rate of cholesterol synthesis and the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase were increased 3- to 14-fold in HSL transfectants grown in sterol replete media. The rate of cholesterol synthesis and the activity of HMG-CoA reductase increased when cells were grown in lipid-depleted media, and remained markedly elevated compared to control cells. These results show that the regulation of LDL receptor expression and cholesterol synthesis can be dissociated through the actions of HSL and suggest multiple control mechanisms for sterol-responsive genes.

Animals↗
PubMed2004

Hormone sensitivity of muscle activation in the sexually dimorphic SNB/BC neuromuscular system of the rat.

Rat penile reflexes are mediated in part by motoneurons in the sexually dimorphic spinal nucleus of the bulbocavernosus (SNB) and a muscle it innervates, the bulbocavernosus (BC). Recruitment in the M-wave component of electromyographic recording in the SNB/BC neuromuscular circuit is sensitive to testosterone and estradiol. To localize the site of the hormonal effect, we recorded muscle activity in a reduced preparation that isolated the peripheral structures involved in generating an M-wave. Castration reduced recruitment amplitude and increased response latency, and treatment with estradiol or the non-aromatizable androgen dihydrotestosterone prevented these changes. Dihydrotestosterone, but not estradiol, maintained BC muscle mass. These results indicate that functional changes in the SNB/BC circuit can result in part from hormonal sensitivity in the neuromuscular periphery and are independent of muscle mass.

Animals↗
PubMed1984

Potential use of analogs of luteinizing hormone-releasing hormones in the treatment of hormone-sensitive neoplasms.

New approaches to the therapy for some endocrine-dependent tumors with analogs of hypothalamic hormones are being developed on the basis of experimental studies in animal models. Analogs of luteinizing hormone-releasing hormones (LH-RH) may open new vistas for the treatment of some hormone-dependent carcinomas. It has been clearly demonstrated that both agonistic and antagonistic analogs of LH-RH can inhibit the growth of rat prostate tumors. A successful treatment of androgen-dependent prostate cancer with agonistic analogs of D-Trp6-LH-RH, D-Ser(But)6des-Gly-NH2(10)-LH-RH ethylamide, and D-Leu6-des-Gly-NH2(10)-LH-RH ethylamide has been documented in several hundred patients. The data accumulated so far from clinical trials suggest that LH-RH agonists can be used as an effective endocrine therapy for prostate carcinoma, therapy avoiding the side effects of estrogen and the psychologic impact of castration. Experimental animal studies and some clinical trials suggest that LH-RH agonists and/or antagonists might also be useful in the treatment of breast cancer. The results of experiments with various hypothalamic analogs in animal models of chondrosarcomas, osteosarcomas, and other tumors appear to be encouraging, but the potential clinical efficacy of LH-RH analogs in the treatment of human hormone-sensitive cancers other than breast and prostate remains to be investigated. The approach to treatment of hormone-dependent tumors based on analogs of hypothalamic hormones might become a useful addition to conventional methods for cancer therapy.

Animals↗
PubMed1988

Alveolar soft-part sarcoma: a hormone-sensitive tumour?

Alveolar soft-part sarcoma is a rare, slow-growing, malignant tumour which metastasizes frequently to the lungs. Treatment with radiotherapy or chemotherapy is largely ineffective, and most patients die within 4 years of developing metastases. We report an unusual patient who survived 9 years after detection of pulmonary metastases. Initial treatment with cytotoxic chemotherapy was ineffective. However, during subsequent treatment with Chinese herbs when she developed galactorrhoea and amenorrhoea (probably due to drug-induced hyperprolactinaemia), her lung metastases regressed, and it is likely that this contributed to her prolonged survival. We hypothesize that alveolar soft-part sarcoma may be a hormone-sensitive tumour, and hormonal manipulation may be an alternative form of treatment which is worth considering.

Adult↗
PubMed1996

Inhibition of hormone-sensitive lipase gene expression by cAMP and phorbol esters in 3T3-F442A and BFC-1 adipocytes.

Hormone-sensitive lipase (HSL) catalyses the rate-limiting step in adipocyte lipolysis. Short-term hormonal regulation of HSL activity is well characterized, whereas little is known about the control of HSL gene expression. We have measured HSL mRNA content of 3T3-F442A and BFC-1 adipocytes in response to the cAMP analogue 8-(4-chlorophenylthio)-cAMP (8-CPT-cAMP) and to the phorbol ester phorbol 12-myristate 13-acetate (PMA) by Northern blot, using a specific mouse cDNA fragment. Treatment of the cells for 12 or 6 h with, respectively, 0.5 mM 8-CPT-cAMP or 1 microM PMA produced a maximal decrease of about 60% in HSL mRNA. These effects were unaffected by the protein-synthesis inhibitor anisomycin, suggesting that cAMP and PMA actions were direct. The reduction in HSL mRNA was accompanied by a reduction in HSL total activity. The intracellular routes that cAMP and PMA follow for inducing such an effect seemed clearly independent. (i) After desensitization of the protein kinase C regulation pathway by a 24 h treatment of the cells with 1 microM PMA, PMA action was abolished whereas cAMP was still fully active. (ii) Treatment with saturating concentrations of both agents produced an additive effect. (iii) The synthetic glucocorticoid dexamethasone had no proper effect on HSL gene expression but potentiated cAMP action without affecting PMA action. cAMP inhibitory action on HSL is unexpected. Indeed, the second messenger of catecholamines is the main activator of HSL by phosphorylation. We envision that a long-term cAMP treatment of adipocytes induces a counter-regulatory process that reduces HSL content and, ultimately, limits fatty acid depletion from stored triacylglycerols.

3T3 Cells↗
PubMed2004

Regulation of hormone-sensitive lipase activity and Ser563 and Ser565 phosphorylation in human skeletal muscle during exercise.

Hormone-sensitive lipase (HSL) catalyses the hydrolysis of myocellular triacylglycerol (MCTG), which is a potential energy source during exercise. Therefore, it is important to elucidate the regulation of HSL activity in human skeletal muscle during exercise. The main purpose of the present study was to investigate the role of 5'AMP-activated protein kinase (AMPK) in the regulation of muscle HSL activity and Ser565 phosphorylation (the presumed AMPK target site) in healthy, moderately trained men during 60 min bicycling (65%). Alpha2AMPK activity during exercise was manipulated by studying subjects with either low (LG) or high (HG) muscle glycogen content. HSL activity was distinguished from the activity of other neutral lipases by immunoinhibition of HSL using an anti-HSL antibody. During exercise a 62% higher (P < 0.01) alpha2AMPK activity in LG than in HG was paralleled by a similar difference (61%, P < 0.01) in HSL Ser565 phosphorylation but without any difference between trials in HSL activity or MCTG hydrolysis. HSL activity was increased (117%, P < 0.05) at 30 min of exercise but not at 60 min of exercise. In both trials, HSL phosphorylation on Ser563 (a presumed PKA target site) was not increased by exercise despite a fourfold increase (P < 0.001) in plasma adrenaline. ERK1/2 phosphorylation was increased by exercise in both trials (P < 0.001) and was higher in LG than in HG both at rest and during exercise (P = 0.06). In conclusion, the present study suggests that AMPK phosphorylates HSL on Ser565 in human skeletal muscle during exercise with reduced muscle glycogen. Apparently, HSL Ser565 phosphorylation by AMPK during exercise had no effect on HSL activity. Alternatively, other factors including ERK may have counterbalanced any effect of AMPK on HSL activity.

AMP-Activated Protein Kinases↗
PubMed1989

Hormone-sensitive lipase is responsible for the neutral cholesterol ester hydrolase activity in macrophages.

Anti-hormone-sensitive lipase (HSL) immunoglobulin selectively immunoprecipitates a single 84 kDa 32P-phosphoprotein from macrophage homogenates previously phosphorylated by cyclic AMP-dependent protein kinase in the presence of [gamma-32P]ATP-Mg. This immunoglobulin also completely removes the neutral cholesterol ester hydrolase activity from macrophage homogenates. These data demonstrate that HSL is responsible for the neutral cholesterol ester hydrolase activity in macrophages and hence plays a key role in cholesterol metabolism in these cells.

Adipose Tissue↗
PubMed1976

A rapid immunological procedure for the isolation of hormonally sensitive rat fat-cell plasma membrane.

1. A rapid method for the isolation of hormonally sensitive rat fat-cell plasma membranes was developed by using immunological techniques. 2. Rabbit anti-(rat erythrocyte) sera were raised and shown to cross-react with isolated rat fat-cells. 3. Isolated rat fat-cells were coated with rabbit anti-(rat erythrocyte) antibodies, homogenized and the homogenate made to react with an immunoadsorbent prepared by covalently coupling donkey anti-(rabbit globulin) antibodies to aminocellulose. Uptake of plasma membrane on to the immunoadsorbent was monitored by assaying the enzymes adenylate cyclase and 5'-nucleotidase and an immunological marker consisting of a 125I-labelled anti-(immunoglobulin G)-anti-cell antibody complex bound to the cells before fractionation. Contamination of the plasma-membrane preparation by other subcellular fractions was also investigated. 4. By using this technique, a method was developed allowing 25-40% recovery of plasma membrane from fat-cell homogenates within 30 min of homogenization. 5. Adenylate cyclase in the isolated plasma-membrane preparation was stimulated by 5 mum-adrenaline.

Adenylyl Cyclases↗
PubMed2001

Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis.

Hormone-sensitive lipase (HSL) is expressed predominantly in white and brown adipose tissue where it is believed to play a crucial role in the lipolysis of stored triglycerides (TG), thereby providing the body with energy substrate in the form of free fatty acids (FFA). From in vitro assays, HSL is known to hydrolyze TG, diglycerides (DG), cholesteryl esters, and retinyl esters. In the current study we have generated HSL knock-out mice and demonstrate three lines of evidence that HSL is instrumental in the catabolism of DG in vivo. First, HSL deficiency in mice causes the accumulation of DG in white adipose tissue, brown adipose tissue, skeletal muscle, cardiac muscle, and testis. Second, when tissue extracts were used in an in vitro lipase assay, a reduced FFA release and the accumulation of DG was observed in HSL knock-out mice which did not occur when tissue extracts from control mice were used. Third, in vitro lipolysis experiments with HSL-deficient fat pads demonstrated that the isoproterenol-stimulated release of FFA was decreased and DG accumulated intracellularly resulting in the essential absence of the isoproterenol-stimulated glycerol formation typically observed in control fat pads. Additionally, the absence of HSL in white adipose tissue caused a shift of the fatty acid composition of the TG moiety toward increased long chain fatty acids implying a substrate specificity of the enzyme in vivo. From these in vivo results we conclude that HSL is the rate-limiting enzyme for the cellular catabolism of DG in adipose tissue and muscle.

Adipose Tissue↗
PubMed2004

Physical association between the adipocyte fatty acid-binding protein and hormone-sensitive lipase: a fluorescence resonance energy transfer analysis.

Previous in vitro studies have established that hormone sensitive lipase (HSL) and adipocyte fatty acid-binding protein (AFABP) form a physical complex that presumably positions the FABP to accept a product fatty acid generated during catalysis. To assess AFABP-HSL interaction within a cellular context, we have used lipocytes derived from 293 cells (C8PA cells) and examined physical association using fluorescence resonance energy transfer. Transfection of C8PA cells with cyan fluorescent protein (CFP)-HSL, yellow fluorescent protein (YFP)-adipocyte FABP, or YFP-liver FABP revealed that under basal conditions each protein was cytoplasmic. In the presence of 20 microm forskolin, CFP-HSL translocated to the triacylglycerol droplet, coincident with BODIPY-FA labeled depots. Fluorescence resonance energy transfer analysis demonstrated that CFP-HSL associated with YFP-adipocyte FABP in both basal and forskolin-treated cells. In contrast, little if any fluorescence resonance energy transfer could be detected between CFP-HSL and YFP-liver FABP. These results suggest that a pre-lipolysis complex containing at least AFABP and HSL exists and that the complex translocates to the surface of the lipid droplet.

Adipocytes↗
PubMed1997

Comparison of hormone-sensitive lipase activity in visceral and subcutaneous human adipose tissue.

The possible role of hormone-sensitive lipase (HSL) in determining regional differences in lipolysis activation in humans was studied in vitro. Small adipose tissue biopsies were obtained from the abdominal sc and omental regions during surgery in 21 subjects spanning a wide range of body mass index (22-50 kg/m2). In lipolysis experiments, isolated fat cells were incubated with lipolytic agents acting at different levels in the lipolytic cascade. The activity and messenger ribonucleic acid expression of HSL were determined. The maximum lipolytic capacity was higher in sc than in omental fat cells as were HSL activity and messenger ribonucleic acid expression. The maximum lipolysis rate was significantly correlated to HSL activity. This is in accordance with the role of HSL as the rate-limiting step of lipolysis. However, adipocytes were 24% larger in the sc than in the omental region, and the lipolysis rate was significantly correlated to fat cell size regardless of either the region of origin or gender. This indicates that the regulation of HSL activity in healthy subjects, which appears to occur at a transcriptional level, is to a large extent dependent on fat cell size.

Abdomen↗
PubMed1999

Metabolic characteristics of a human hepatoma cell line stably transfected with hormone-sensitive lipase.

Clones of HepG2 cells were selected that stably express the cDNA for hormone-sensitive lipase (HSL). When cells were cultured in the presence of labelled extracellular oleate, accumulation of labelled fatty acid as cellular triacylglycerol (TAG) was significantly lower in the transfectants compared with the wild-type cells. There was no change in the net rate of phospholipid (PL) synthesis. Culture of cells containing isotopically prelabelled TAG resulted in a greater net loss of TAG from the transfected cells than from the wild-type cells. The excess loss of labelled TAG was primarily due to an increased TAG fatty acid oxidation. Free fatty acid release into the medium was not increased in the transfectants, nor was the very low rate of lipoprotein lipid secretion. Also, there was no increased net trafficking of fatty acids from TAG into PLs. Changes in the 3H:14C ratio of TAG prelabelled with [3H]glycerol and [14C]oleate suggested that none of excess TAG fatty acid released in the transfected cells underwent intracellular re-esterification to TAG prior to oxidation. The results suggest that fatty acids mobilized by HSL are directed immediately into the oxidative pathway and are not available for biosynthetic processes. It appears likely, therefore, that intracellular TAG-derived fatty acids which enter the oxidative pathway exist in a different compartment from those that are directed towards synthesis.

Carcinoma, Hepatocellular↗
PubMed2003

Hormone-sensitive lipase is required for high-density lipoprotein cholesteryl ester-supported adrenal steroidogenesis.

Steroid hormones are synthesized using cholesterol as precursor, with a substantial portion supplied by the selective uptake of lipoprotein-derived cholesteryl esters. Adrenals express a high level of neutral cholesteryl ester hydrolase activity, and recently hormone-sensitive lipase (HSL) was shown to be responsible for most adrenal neutral cholesteryl ester hydrolase activity. To determine the functional importance of HSL in adrenal steroidogenesis, adrenal cells were isolated from control and HSL-/- mice, and the in vitro production of corticosterone was quantified. Results show that, even though adrenal cholesteryl ester content was substantially elevated in both male and female HSL-/- mice, basal corticosterone production was reduced approximately 50%. The maximum corticosterone production induced by dibutyryl cAMP, and lipoproteins was approximately 75-85% lower in adrenal cells from HSL-/- mice compared with control. There is no intrinsic defect in the conversion of cholesterol into steroids in HSL-/- mice. Dibutyryl cAMP-stimulated conversion of high-density lipoprotein cholesteryl esters into corticosterone was reduced 97% in HSL-/- mice. An increase in low-density lipoprotein receptor expression appears to be one of the compensatory mechanisms for cholesterol delivery in HSL-/- mice. These findings suggest that HSL is functionally linked to the selective pathway and is critically involved in the intracellular processing and availability of cholesterol for adrenal steroidogenesis.

Adrenal Glands↗
PubMed2026

Non-Cancer Causes of Death in Patients With Metastatic Hormone-Sensitive Prostate Cancer: A Real-World Analysis.

BACKGROUND: As overall survival improves in metastatic hormone-sensitive prostate cancer (mHSPC), non-cancer causes of death are increasingly relevant. METHODS: We conducted a real-world multicenter study of patients diagnosed with mHSPC treated with ADT alone or in combination. Causes of death before progression to castration-resistant prostate cancer (CRPC) were classified as cancer- or non-cancer-related. Deaths were classified as non-cancer-related if they occurred in the absence of cancer progression. RESULTS: Among 565 patients, 35 (6.2%) died from non-cancer-related causes without disease progression, mainly infections (34%) and cardiovascular events (20%). CONCLUSIONS: Non-cancer mortality represents a meaningful proportion of deaths in mHSPC, supporting systematic cardiovascular risk evaluation and infection-prevention strategies.

Humans↗