The presence and role of hormone-sensitive lipase in heart muscle

Small, C.E.; Garton, Andrew J.; Yeaman, Stephen J.

doi:10.1042/bj2580067

Cited by 69 publications

(33 citation statements)

References 30 publications

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“…Conversely, insulin inhibits the phosphorylation and therefore the activity of HSL, in part, by reducing cAMP levels (32). Only recently, this same enzyme has been identified and characterized in small quantities in muscle tissue (33,34) and it is hypothesized that it plays a role in intracellular triacylglycerol hydrolysis working in concert with extracellular muscle lipoprotein lipase on the endothelial surface (35). However, the physiological importance and the potential regulation of muscle HSL has yet to be characterized.…”

Section: Discussionmentioning

confidence: 99%

Interstitial fluid concentrations of glycerol, glucose, and amino acids in human quadricep muscle and adipose tissue. Evidence for significant lipolysis in skeletal muscle.

Maggs¹,

Jacob²,

Rife³

et al. 1995

J. Clin. Invest.

163

120

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To determine the relationship between circulating metabolic fuels and their local concentrations in peripheral tissues we measured glycerol, glucose, and amino acids by microdialysis in muscle and adipose interstitium of 10 fasted, nonobese human subjects during (a) baseline, (b) euglycemic hyperinsulinemia (3 mU/kg per min for 3 h) and, (c) local norepinephrine reuptake blockade (NOR). At baseline, interstitial glycerol was strikingly higher (P < 0.0001) in muscle (3710 jLM) and adipose tissue (2760 ,uM) compared with plasma (87 ,LM), whereas interstitial glucose (muscle 3.3, fat 3.6 mM) was lower (P < 0.01) than plasma levels (4.8 mM). Taurine, glutamine, and alanine levels were higher in muscle than in adipose or plasma (P < 0.05). Euglycemic hyperinsulinemia did not affect interstitial glucose, but induced a fall in plasma glycerol and amino acids paralleled by similar changes in the interstitium of both tissues. Local NOR provoked a fivefold increase in glycerol (P < 0.001) and twofold increase in norepinephrine (P < 0.01) in both muscle and adipose tissues. To conclude, interstitial substrate levels in human skeletal muscle and adipose tissue differ substantially from those in the circulation and this disparity is most pronounced for glycerol which is raised in muscle as well as adipose tissue. In muscle, insulin suppressed and NOR increased interstitial glycerol concentrations. Our data suggest unexpectedly high rates of intramuscular lipolysis in humans that may play an important role in fuel metabolism. (J. Clin. Invest. 1995. 96:370-377.)

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Section: Discussionmentioning

confidence: 99%

Interstitial fluid concentrations of glycerol, glucose, and amino acids in human quadricep muscle and adipose tissue. Evidence for significant lipolysis in skeletal muscle.

Maggs¹,

Jacob²,

Rife³

et al. 1995

J. Clin. Invest.

163

120

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“…In contrast to skeletal muscle, the metabolic requirements of cardiac muscle are met by an extremely high lipolytic turnover of myocardial TG (54). Cardiac muscle TG breakdown is under acute hormonal control, and the discovery of HSL in cardiomyocytes (2,55) suggests that HSL is responsible for the intracellular lipolysis of TG. Our data confirm the presence of HSL in cardiomyocytes and assign it an important role in the catabolism of DG.…”

Section: Discussionmentioning

confidence: 99%

Hormone-sensitive Lipase Deficiency in Mice Causes Diglyceride Accumulation in Adipose Tissue, Muscle, and Testis

Haemmerle¹,

Zimmermann²,

Hayn³

et al. 2002

Journal of Biological Chemistry

542

532

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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 isoproterenolstimulated 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. Hormone-sensitive lipase (HSL)1 is thought to be a key enzyme for the mobilization of triglycerides (TG) deposited in adipose tissue. Human HSL is composed of 775 amino acids that are encoded by a 2.9-kb mRNA transcribed from a single gene composed of 9 exons (1, 2). The mouse and the human genes are similar in size and share a high degree of sequence homology. A tissue-specific size variation has been observed in testis where an additional exon 13 kb upstream of exon 1 in adipose tissue gives rise to a 3.9-kb mRNA and a 1076-amino acid protein (3). The molecular basis of size variations in HSL mRNA in muscle, macrophages, and ovaries is unknown.HSL-mediated lipolysis is strictly controlled by hormones. The enzyme is activated by catecholamines and other lipolytic hormones upon phosphorylation by the cAMP-dependent protein kinase A and the lipotransin-mediated translocation of the enzyme from the cytoplasm to the lipid droplet (4 -6). Insulin, the major antilipolytic hormone, inhibits HSL through phosphodiesterase-3-dependent cAMP degradation and interference with the lipotransin-mediated enzyme translocation. Accordingly, mice with elevated protein kinase A activity exhibit increased lipolysis and a lean phenotype (7). Absence of perilipin in mice also resulted in leanness through constitutive activation of HSL (8). Conversely, mice that lack the insulin receptor substrate 2 become obese (9). These results imply that imbalances between lipid accumulation and fat mobilizati...

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“…mg-'. , K,, 19 For cyclic-AMP-dependent protein kinase, thc K , for the SSMS peptide was z 20-fold higher than it was for the AMPactivated protein kinase and the SAMS was not phosphorylated al all (Fig. 1).…”

Section: Phosphoryhtion Qf Synthetic Peptidesmentioning

confidence: 99%

“…Lung is a mixture of epithelial cells, smooth muscle, and blood vessel endothelial cells, and the type IT epithelial cells in particular are active in synthesis of fatty acids required lor the production of surfactant [18]. Heart myocytes store triglycerides as an energy reserve and are another tissue that contains the hormone-sensitive lipase/cholesterol csterase [19]. The finding that the kinase activity is expressed in macrophages is particularly interesting because arterial wall macrophages are believed to be the precursors of the 'foam' cells which accumulate massive amounts of cholesterol ester in atherosclerosis [20].…”

Section: Dtscussionmentioning

confidence: 99%

Tissue distribution of the AMP‐activated protein kinase, and lack of activation by cyclic‐AMP‐dependent protein kinase, studied using a specific and sensitive peptide assay

Davies

Carling

Hardie

1989

European Journal of Biochemistry

411

327

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1. We have synthesized two peptides, one based on the exact sequence around the unique site (Ser79) for thc AMP-activated protein kinase on rat acetyl-CoA carboxylase (SSMS peptide) and another in which the serine residue corresponding to the site for cyclic-AMP-dependent protein kinase (Ser77) was replaced by alanine (SAMS peptide).2. Both peptides were phosphorylated with similar kinetics by the AMP-activated protein kinase, but only the SSMS peptide was a substrate for cyclic-AMP-dependent protein kinase. The SAMS peptide was not phosphorylated by any of five other purified protein kinases tested.3. The K,,, of AMP-activated protein kinase for the SAMS peptidc is higher than that for acetyl-CoA carboxylase, but the V,,, for peptide phosphorylation is 2.5 times higher than that of its parent protein. This peptide therefore gives a convenient and sensitive assay for the AMP-activated protein kinase.4. Acetyl-CoA-carboxylase kinase and peptide kinase activities copurify through six steps from a postmitochondria1 supernatant of rat liver, showing that the SAMS peptide is a specific substrate for the AMPaclivated protein kinasc in this tissuc. Wc could not demonstrate AMP-depcndence of the kinase activity in crude preparations, apparently due to endogenous AMP remaining bound to the enzyme. However, 8-bromoadenosine 5-monophosphate (Br8AMP) is a partial agonist at the allosteric (AMP) site, and inhibition by 2 mM Br'AMP can be used to test that one is measuring the AMP-stimulated form of the kinase.5. Using this approach, we have examined the kinase activity in nine different rat tissues, plus a mousc macrophage cell line, iind find that there is a correlation betwcen tissucs expressing significant levels of peptide kinase activity and those active in the synthesis or storage of lipids.6. We also use the peptide assay to show that cyclic AMP-dependent protein kinase does not activate purified AMP-activated protein kinase, and does not affect the activation of partially purified AMP-activated protein kinase by endogenous kinase kinase.The AMP-activated protein kinase is a recently recognized multisubstrate kinase which appears to play a central role in regulation of fatty acid and cholesterol metabolism [l]. The kinase was originally recognized for its ability to inactivate 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase [2], but has recently also been shown to phosphorylate and inactivate acetyl-CoA carboxylase [3,4]. and to phosphorylatc hormone-sensitive lipase which blocks activation of that enzyme by cyclic-AMP-dependent protein kinase [5]. The kinase is activated by AMP, and also by phosphorylation catalyzed by a distinct 'kinase kinase' [3].The existing assays for this kinase either involve its ability to inactivate microsomal HMG-CoA reductase in a time-and

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The presence and role of hormone-sensitive lipase in heart muscle

Cited by 69 publications

References 30 publications

Interstitial fluid concentrations of glycerol, glucose, and amino acids in human quadricep muscle and adipose tissue. Evidence for significant lipolysis in skeletal muscle.

Interstitial fluid concentrations of glycerol, glucose, and amino acids in human quadricep muscle and adipose tissue. Evidence for significant lipolysis in skeletal muscle.

Hormone-sensitive Lipase Deficiency in Mice Causes Diglyceride Accumulation in Adipose Tissue, Muscle, and Testis

Tissue distribution of the AMP‐activated protein kinase, and lack of activation by cyclic‐AMP‐dependent protein kinase, studied using a specific and sensitive peptide assay

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