Specific Inhibition of Hormone-Sensitive Lipase Improves Lipid Profile while Reducing Plasma Glucose

Claus, Thomas H.; Lowe, Derek; Liang, Yin; Salhanick, Arthur I.; Lubeski, Christine Keiper; Yang, Ling; Lemoine, Lynn; Zhu, Jian; Clairmont, Kevin B.

doi:10.1124/jpet.105.086926

Cited by 79 publications

(55 citation statements)

References 36 publications

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“…The role of lipases in insulin secretion has been emphasised by islet studies, using different pharmacological inhibitors [21,42]. Recently, a specific inhibitor of HSL, 5-(2H)-isoxazolonyl urea, was shown to significantly inhibit insulin secretion in rat islets [14]. Together, these data suggest an important role for HSL in stimulus-secretion coupling and insulin secretion.…”

Section: Discussionmentioning

confidence: 71%

“…To this end, LC-CoAs have been shown to stimulate insulin secretion, possibly via the activation of protein kinase C [10], direct interaction with the exocytotic machinery [11] or via activation of the ATP-sensitive K + channel [12]. The critical role of lipolysis has been further highlighted by studies using lipase inhibitors: thus orlistat, a pan-lipase inhibitor, blocks lipolysis and insulin secretion in rat islets [13], while a selective inhibitor of HSL has been shown to inhibit insulin secretion from rat islets [14]. Moreover, a positive correlation between lipolysis and insulin secretion exists in INS-1 cells and mouse islets [15].…”

Section: Introductionmentioning

confidence: 99%

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A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

et al. 2008

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Aims/hypothesis The enzyme hormone-sensitive lipase (HSL) is produced and is active in pancreatic beta cells. Because lipids are known to play a crucial role in normal control of insulin release and in the deterioration of beta cell function, as observed in type 2 diabetes, actions of HSL in beta cells may be critical. This notion has been addressed in different lines of HSL knockout mice with contradictory results. Methods To resolve this, we created a transgenic mouse lacking HSL specifically in beta cells, and characterised this model with regard to glucose metabolism and insulin secretion, using both in vivo and in vitro methods. Results We found that fasting basal plasma glucose levels were significantly elevated in mice lacking HSL in beta cells. An IVGTT at 12 weeks revealed a blunting of the initial insulin response to glucose with delayed elimination of the sugar. Additionally, arginine-stimulated insulin secretion was markedly diminished in vivo. Investigation of the exocytotic response in single HSL-deficient beta cells showed an impaired response to depolarisation of the plasma membrane. Beta cell mass and islet insulin content were increased, suggesting a compensatory mechanism, by which beta cells lacking HSL strive to maintain normoglycaemia. Conclusions/interpretation Based on these results, we suggest that HSL, which is located in close proximity of the secretory granules, may serve as provider of a lipidderived signal essential for normal insulin secretion.

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Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

et al. 2008

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“…Isoproterenol (specific agonist of ␤-adrenergic receptor) and CL-316243 (CL) (Sigma) were dissolved in H 2 O. BAY 59-9435 (BAY, dissolved in 0.5% methylcellulose), a highly selective HSL inhibitor (28 -30), was chemically synthesized, as described (30). Novo 13f, another highly selective HSL inhibitor (31), was a generous gift of Dr. Christian Fledelius (Novo Nordisk A/S).…”

Section: Methodsmentioning

confidence: 99%

Adipocyte Lipolysis-stimulated Interleukin-6 Production Requires Sphingosine Kinase 1 Activity

Zhang

Mottillo

Zhao

et al. 2014

Journal of Biological Chemistry

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Background: Lipolysis contributes to adipose inflammation. Results: Lipolysis up-regulates sphingosine kinase 1 (SphK1) in adipocytes. Modulation of SphK1 regulates adipose lipolysisstimulated interleukin 6 production. Conclusion: SphK1 plays a pivotal role in adipose inflammation. Significance: Identification of a role for SphK1 in lipolysis-triggered adipose inflammation. Targeting SphK1 provides a novel intervention for adipose inflammation and associated metabolic syndromes.

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“…Inhibition of HSL by inhibitor decreases the plasma fatty acid level in vivo. [25] Treating of adipose tissue with the glucose and insulin results in elevated lipolysis and HSL level is maintained. [26] Inhibition of HSL results in accomplished non-appearance of discharge of FA from AT.…”

Section: Discussionmentioning

confidence: 99%

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Abilash

2017

AJP

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Introduction: Adipose tissue is an endocrine organ which is made up of special connective tissue. The major task of this tissue is to accumulate the energy in the form of triacylglycerol (TAG). Adipogenesis is the process of formation of the preadipocyte into the mature adipocyte. Normally adipose tissue is of two types, namely, white adipose tissue (WAT) and brown adipose tissue (BAT). An important role WAT is to store TAG and the significant responsibility BAT is production of heat (thermogenesis). Fat accumulation is identified by the balance between the fat synthesis such as adipogenesis and the fat break down such as lipolysis. When there is excessive amount of intake of food, elevated plasma carbohydrate and triglyceride are involved in lipogenesis in adipose tissue. During fasting condition, there is a process called lipolysis which releases fatty acids and glycerol into the circulation. Our aim is to investigate the single nucleotide polymorphisms (SNP) analysis of genes participated in maintenance of adipose tissue such as hormone sensitive lipase monoglyceride lipase and adiponectin. Materials and Methods: In silico analysis using sorting intolerant from tolerant (SIFT), polyphen 2 was performed for the genes concerned in maintaining adipose tissue homeostasis. Results: SNPs were analyzed for all the genes. Benign and damaging SNPs were identified using SIFT and polyphen 2. Conclusion: As SNPs show suppressed stability, damaging and benign character, they can be further utilized for in vivo studies to determine the role of these genes in adipose tissue homeostasis.

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Specific Inhibition of Hormone-Sensitive Lipase Improves Lipid Profile while Reducing Plasma Glucose

Cited by 79 publications

References 36 publications

A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

Adipocyte Lipolysis-stimulated Interleukin-6 Production Requires Sphingosine Kinase 1 Activity

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