Defective Lipolysis and Altered Energy Metabolism in Mice Lacking Adipose Triglyceride Lipase

Haemmerle, Guenter; Lass, Achim; Zimmermann, R.; Gorkiewicz, Gregor; Meyer, Carola W.; Rozman, Jan; Heldmaier, Gerhard; Maier, Robert; Theussl, Christian; Eder, Sandra; Kratky, Dagmar; Wagner, Erwin F.; Klingenspor, Martin; Höefler, Gerald; Zechner, Rudolf

doi:10.1126/science.1123965

Cited by 1,164 publications

(1,296 citation statements)

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“…The accumulation of diglycerides (DG) in the adipose tissue of HSL knockout mice suggests that HSL is the rate limiting enzyme for the hydrolysis of DG and not TG (Haemmerle et al, 2002). Adipose TG lipase (ATGL) has been suggested to be the key enzyme involved in TG hydrolysis in the adipose tissue (Schweiger et al, 2006;Haemmerle et al, 2006;Zimmermann et al, 2004). TG lipolysis was shown to be severely impaired in ATGL-deficient mice accumulating large amount of fat in major organs and leading to premature death .…”

Section: Introductionmentioning

confidence: 99%

A computational model of adipose tissue metabolism: Evidence for intracellular compartmentation and differential activation of lipases

Kim

Saidel

Kalhan

2008

Journal of Theoretical Biology

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Regulation of lipolysis in adipose tissue is critical to whole body fuel homeostasis and to the development of insulin resistance. Due to the challenging nature of laboratory investigations of regulatory mechanisms in adipose tissue, mathematical models could provide a valuable adjunct to such experimental work. We have developed a computational model to analyze key components of adipose tissue metabolism in vivo in human in the fasting state. The various key components included triglyceride-fatty acid cycling, regulation of lipolytic reactions, and glyceroneogenesis. The model, consisting of spatially lumped blood and cellular compartments, included essential transport processes and biochemical reactions. Concentration dynamics for major substrates were described by mass balance equations. Model equations were solved numerically to simulate dynamic responses to intravenous epinephrine infusion. Model simulations were compared with the corresponding experimental measurements of the arteriovenous difference across the abdominal subcutaneous fat bed in humans. The model can simulate physiological responses arising from the different expression levels of lipases. Key findings of this study are as follows: (1) Distinguishing the active metabolic subdomain (~3% of total tissue volume) is critical for simulating data. (2) During epinephrine infusion, lipases are differentially activated such that diglyceride breakdown is ~4 times faster than triglyceride breakdown. (3) Glyceroneogenesis contributes more to glycerol-3-phosphate synthesis during epinephrine infusion when pyruvate oxidation is inhibited by a high acetyl-CoA/free-CoA ratio.

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Section: Introductionmentioning

confidence: 99%

A computational model of adipose tissue metabolism: Evidence for intracellular compartmentation and differential activation of lipases

Kim

Saidel

Kalhan

2008

Journal of Theoretical Biology

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“…Weak phospholipase activity has been demonstrated for ATGL, GS-2, and adiponutrin (5). To date, deletion mutants in mice only have been generated for ATGL (9). ATGL-deficient animals exhibited a major defect in the catabolism of stored TG in adipose and non-adipose tissues resulting in a multisystemic TG accumulation, obesity, cardiac dysfunction, and premature death.…”

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confidence: 99%

Identification of an Insulin-regulated Lysophospholipase with Homology to Neuropathy Target Esterase

Kienesberger

Lass

Preiss-Landl

et al. 2008

Journal of Biological Chemistry

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Neuropathy target esterase (NTE) is a member of the family of patatin domain-containing proteins and exhibits phospholipase activity in brain and cultured cells. NTE was originally identified as target enzyme for organophosphorus compounds that cause a delayed paralyzing syndrome with degeneration of nerve axons. Here we show that the structurally related murine protein NTErelated esterase (NRE) is a potent lysophospholipase. The enzyme efficiently hydrolyzes sn-1 esters in lysophosphatidylcholine and lysophosphatidic acid. No lipase activity was observed when triacylglycerols, cholesteryl esters, retinyl esters, phosphatidylcholine, or monoacylglycerol were used as substrates. Although NTE is predominantly expressed in the nervous system, we found the highest NRE mRNA levels in testes, skeletal muscle, cardiac muscle, and adipose tissue. Induction of NRE mRNA concentrations in these tissues during fasting suggested a nutritional regulation of enzyme expression and, in accordance with this observation, insulin reduced NRE mRNA levels in a dose-dependent manner in 3T3-L1 adipocytes. A green fluorescent protein-NRE fusion protein colocalized to the endoplasmic reticulum and lipid droplets. Thus, NRE is a previously unrecognized ER-and lipid droplet-associated lysophospholipase. Regulation of enzyme expression by the nutritional status and insulin suggests a role of NRE in the catabolism of lipid precursors and/or mediators that affect energy metabolism in mammals.

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“…Un double déficit en HSL et en ATGL provoque la perte de 90 % de l'activité acylhydrolase, démontrant ainsi que ces deux enzymes sont les principales lipases en charge de la lipolyse. Ainsi, une accumulation de lipides dans le tissu adipeux blanc et brun ainsi que dans d'autres tissus non adipeux est retrouvée chez la souris invalidée pour l'ATGL, avec une accumulation plus importante au niveau du coeur, provoquant de sérieuses complications de type cardiomyopathies chez ces animaux [41]. Chez l'homme, des mutations du gène sont responsables d'une myopathie liée à un excès de lipides neutres dans les muscles squelettiques et le coeur [42,43].…”

Section: L'adipose Triglyceride Lipase (Atgl Pnpla2)unclassified

Les protéines à domaine patatine

Baulande¹,

Langlois²

2010

Med Sci (Paris)

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Identification des enzymes à domaine patatineLes lipides ont des rôles essentiels et multiples dans les cellules, que ce soit dans le maintien des structures intracellulaires et le transport vésiculaire, la régulation de l'équilibre énergétique et la génération de seconds messagers participant à des mécanismes de signalisation cellulaire. Ces dernières années, la découverte de l'ATGL (adipose triglyceride lipase) et de l'adiponutrine, deux protéines adipocytaires, a permis d'identifier une nouvelle famille d'enzymes intervenant dans le méta-bolisme lipidique et ayant un domaine enzymatique commun appelé patatine ou PNPLA. La mise en évidence de ces nouvelles enzymes dotées d'activités lipase/ transacylase met en lumière de nouveaux mécanismes de la régulation du métabolisme lipidique d'importance fondamentale chez les organismes supérieurs.> Les avancées prodigieuses dans le séquençage des génomes ont permis de mettre en évidence nombre de nouveaux gènes jusqu'alors inconnus, ouvrant ainsi un vaste chantier d'investigations relatives à la caractérisation de leurs fonctions biologiques. L'ère de la génomique fonctionnelle succède donc à celle du séquençage des géno-mes avec comme enjeu majeur de permettre une meilleure compréhension de la physiologie cellulaire. Ces dernières années, plusieurs protéines partageant un même domaine protéique appelé patatine, ou domaine PNPLA (patatin-like phospholipase domain), ont été découvertes.

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Defective Lipolysis and Altered Energy Metabolism in Mice Lacking Adipose Triglyceride Lipase

Cited by 1,164 publications

References 25 publications

A computational model of adipose tissue metabolism: Evidence for intracellular compartmentation and differential activation of lipases

A computational model of adipose tissue metabolism: Evidence for intracellular compartmentation and differential activation of lipases

Identification of an Insulin-regulated Lysophospholipase with Homology to Neuropathy Target Esterase

Les protéines à domaine patatine

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