Regulation of hormone-sensitive lipase in islets

Shen, Wen-Jun; Yu, Long-Chuan; Wang, Jenny; Harada, Kenji; Patel, Shushma; Michie, Sara A.; Osuga, Jun-ichi; Ishibashi, Shun; Kraemer, Fredric B.

doi:10.1016/j.diabres.2006.05.001

Cited by 8 publications

(3 citation statements)

References 48 publications

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“…The size of pancreatic islets is determined by the metabolic state. Under conditions of increased metabolic load, increased basal serum insulin levels, or obesity-associated insulin resistance, the islet size tends to become larger (Harada et al, 2003;Rhodes, 2005;Roduit et al, 2001;Shen et al, 2007). In agreement with the observed improved insulin and glucose tolerance in TGH-deficient mice, the islets in these mice were significantly smaller compared to WT mice.…”

Section: Cell Metabolismsupporting

confidence: 72%

Loss of TGH/Ces3 in Mice Decreases Blood Lipids, Improves Glucose Tolerance, and Increases Energy Expenditure

et al. 2010

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Excessive accumulation of triacylglycerol in peripheral tissues is tightly associated with obesity and has been identified as an independent risk factor for insulin resistance, type 2 diabetes, and cardiovascular complications. Here we show that ablation of carboxylesterase 3 (Ces3)/triacylglycerol hydrolase (TGH) expression in mice (Tgh(-/-)) results in decreased plasma triacylglycerol, apolipoprotein B, and fatty acid levels in both fasted and fed states. Despite the attenuation of very low-density lipoprotein secretion, TGH deficiency does not increase hepatic triacylglycerol levels. Tgh(-/-) mice exhibit increased food intake, respiratory quotient, and energy expenditure without change in body weight. These metabolic changes are accompanied by improved insulin sensitivity and glucose tolerance. Tgh(-/-) mice have smaller sized pancreatic islets but maintain normal glucose-stimulated insulin secretion. These studies demonstrate the potential of TGH as a therapeutic target for lowering blood lipid levels.

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Section: Cell Metabolismsupporting

confidence: 72%

Loss of TGH/Ces3 in Mice Decreases Blood Lipids, Improves Glucose Tolerance, and Increases Energy Expenditure

et al. 2010

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“…Indeed, we detected strong HSL expression in pancreatic islets and PanIN lesions and reduced expression of LIPE (the gene encoding HSL) in pancreatic tissue of patients with PDAC is associated with decreased overall survival [ 26 ]. HSL deficiency in pancreatic islets may thereby explain the observed reduction in insulin of KC;Hsl −/− mice in our study, as HSL has been described to be important in glucose-stimulated insulin secretion in pancreatic beta cells [ 27 ]. HSL deficiency in the pancreas was accompanied by reduced TG and FFA levels, indicating a prominent role of HSL (and a possible absence of additional neutral lipases) in FFA release from intracellular TG depots in the pancreas.…”

Section: Discussionmentioning

confidence: 64%

Deficiency in hormone-sensitive lipase accelerates the development of pancreatic cancer in conditional KrasG12D mice

Chang

Jung

et al. 2018

BMC Cancer

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BackgroundHormone sensitive lipase (HSL) is a neutral lipase that preferentially catalyzes the hydrolysis of diacylglycerol contributing to triacylglycerol breakdown in the adipose tissue. HSL has been implicated to play a role in tumor cachexia, a debilitating syndrome characterized by progressive loss of adipose tissue. Consequently, pharmacological inhibitors of HSL have been proposed for the treatment of cancer-associated cachexia. In the present study we used the conditional KrasG12D (KC) mouse model of pancreatic ductal adenocarcinoma (PDAC) with a deficiency in HSL to determine the impact of HSL suppression on the development of PDAC.MethodsKC;Hsl+/+ and KC;Hsl−/− mice were fed standard rodent chow for 20 weeks. At sacrifice, the incidence of PDAC was determined and inflammation in the mesenteric adipose tissue and pancreas was assessed histologically and by immunofluorescence. To determine statistical significance, ANOVA and two-tailed Student’s t-tests were performed. To compare PDAC incidence, a two-sided Fisher’s exact test was used.ResultsCompared to KC;Hsl+/+ mice, KC;Hsl−/− mice gained similar weight and displayed adipose tissue and pancreatic inflammation. In addition, KC;Hsl−/− mice had reduced levels of plasma insulin and leptin. Importantly, the increased adipose tissue and pancreatic inflammation was associated with a significant increase in PDAC incidence in KC;Hsl−/− mice.ConclusionsHSL deficiency is associated with adipose tissue and pancreatic inflammation and accelerates PDAC development in the KC mouse model.

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“…Although HSL was initially identified as an adipose-specific lipase, it has been clarified that HSL is also expressed and functions in a wide variety of organs and cells, including heart, skeletal muscle, adrenal glands, testes, ovaries, intestines and liver [7,8,10,11]. HSL was also identified in pancreatic b-cells [12], and several laboratories reported the relationship between the HSL-mediated lipolysis and insulin secretory machinery using rodent models without coming to consensus [13][14][15][16][17].…”

mentioning

confidence: 99%