Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome

Lass, Achim; Zimmermann, R.; Haemmerle, Guenter; Riederer, Monika; Schoiswohl, Gabriele; Schweiger, Martina; Kienesberger, Petra C.; Strauß, Juliane Gertrude; Gorkiewicz, Gregor; Zechner, Rudolf

doi:10.1016/j.cmet.2006.03.005

Cited by 791 publications

(891 citation statements)

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“…Our data showed that the phosphorylation of HSL and expression of CGI-58 were increased in the tissue of the RRM rats. Phosphorylation of HSL is required for the activity of the enzyme and is mainly regulated by protein kinase A. CGI-58 is localized to lipid [24] . This information suggests that multiple pathways might be involved in the activation of HSL and ATGL under conditions of CKD.…”

Section: Discussionmentioning

confidence: 99%

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The effect of inhibition of endoplasmic reticulum stress on lipolysis in white adipose tissue in a rat model of chronic kidney disease

et al. 2014

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Aim: Lipolysis in fat tissue plays an important role in the development of metabolic disturbances, a characteristic feature of chronic kidney disease (CKD). In the present study, we tested the hypothesis that the inhibition of endoplasmic reticulum (ER) stress could alleviate lipolysis in white adipose tissue in a rat model of CKD. Methods: A rat model of CKD was established by a method of reduced renal mass (RRM). Lipolysis was measured as the release of glycerol in ex vivo fat pads and cultured primary adipocytes. The activity of lipases and markers of ER stress were measured by Western blotting and immunoprecipitation. Results: Our data showed that lipolysis in visceral white adipose tissue was increased in RRM rats compared with control rats. In addition, increased phosphorylation of hormone-sensitive lipase (HSL) and binding of adipose triglyceride lipase (ATGL) to comparative gene identification-58 (CGI-58) protein were observed in the RRM rats. The phosphorylation of ER stress markers, including IRE1α, PERK, and eukaryotic initiation factor (eIF) 2α, and the expression of ER stress marker 78 kDa glucose-regulated protein (GRP78) were significantly increased in RRM rats. Treatment with an inhibitor of ER stress partially but significantly alleviated lipolysis, and this alleviation was accompanied by reduced binding of ATGL to CGI-58. Conclusion: Our results showed that enhanced lipolysis and ER stress occurred in visceral white adipose tissue in a rat model of CKD. Moreover, inhibition of ER stress significantly alleviated lipolysis. These findings suggest that ER stress is a potential therapeutic target for the metabolic disturbances associated with CKD.

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Section: Discussionmentioning

confidence: 99%

“…(CGI-58) [24] , a lipid droplet-associated protein that promotes the hydrolysis of triglycerides by activating ATGL. Therefore, we measured the abundance of ATGL and CGI-58.…”

Section: Enhanced Lipolysis In White Adipose Tissue In Rrm Ratsmentioning

confidence: 99%

The effect of inhibition of endoplasmic reticulum stress on lipolysis in white adipose tissue in a rat model of chronic kidney disease

et al. 2014

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“…In addition to perilipin, a number of PAT (perilipin/adipophilin/TIP47) family proteins have been identified on the lipid droplet and may contribute to the regulation of lipolysis [62]. Comparative gene identification (CGI)-58, another lipid droplet-associated protein, has been shown to colocalize with perilipin [63,64] and increase lipolysis by activating desnutrin/ATGL (discussed in the next section) [65].…”

Section: Hydrolysis Of Triacylglycerolmentioning

confidence: 99%

Triacylglycerol Metabolism In Adipose Tissue

et al. 2007

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Triacylglycerol (TAG) in adipose tissue serves as the major energy storage form in higher eukaryotes. Obesity, resulting from excess white adipose tissue, has increased dramatically in recent years resulting in a serious public health problem. Understanding of adipocyte-specific TAG synthesis and hydrolysis is critical to the development of strategies to treat and prevent obesity and its closely associated diseases, for example, Type 2 diabetes, hypertension and atherosclerosis. In this review, we present an overview of the major enzymes in TAG synthesis and lipolysis, including the recent discovery of a novel adipocyte TAG hydrolase. Keywords1-acylglycerol-3-phosphate acyltransferase; desnutrin/adipose triglyceride lipase; diacylglycerol acyltransferase; glycerol-3-phosphate acyltransferase; hormone-sensitive lipase; lipolysis; phosphatidic acid phosphatase; triacylglycerol White adipose tissue (WAT) is the major energy reserve in higher eukaryotes. The primary purposes of WAT are synthesis and storage of triacylglycerol (TAG) in periods of energy excess, and hydrolysis of TAG to generate fatty acids for use by other organs during periods of energy deprivation [1]. Adipose tissue also secretes adipokines that regulate energy intake and metabolism.The prevalence of obesity resulting from excess WAT has increased dramatically in recent years resulting in a serious public health problem, since obesity is closely associated with a number of disorders including Type 2 diabetes, hypertension and atherosclerosis [2]. While † Author for correspondence, University of California, Department of Nutritional Sciences & Toxicology, Berkeley, CA 94720, USA, adipocyte number has been shown to increase (hyperplasia) in morbid obesity, obesity is primarily attributed to adipocyte hypertrophy that occurs when TAG synthesis (esterification) exceeds TAG breakdown (lipolysis), resulting in elevated TAG storage [1]. Although it has been postulated that large adipocyte size may contribute to insulin resistance, the molecular mechanism is not clear.Paradoxically, the metabolic abnormalities typically found in obesity are also associated with lipodystrophies that are characterized by selective loss of adipose tissue from particular regions of the body [3][4][5][6]. Although the underlying molecular mechanisms are not clear, metabolic complications may result from ectopic storage of TAG in tissues such as the liver and muscle [7][8][9]. A proper capacity for TAG storage in adipocytes is clearly important for normal metabolic regulation. In view of the wide range of health problems associated with improper fat storage and release, it is critical to understand adipocyte-specific regulation of TAG synthesis and hydrolysis. Biosynthesis of triacylglycerolThe synthesis of phosphatidic acid and its subsequent conversion to TAG was described more than 40 years ago by Kennedy and coworkers [10], and is summarized in Figure 1. The initial committal step in this pathway is the formation of lysophosphatidic acid (1-acylglycerol-3-phosphate)...

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“…Also, ATGL and PNPLA3 share the highest homology of any patatin domain proteins. 2 Binding of ATGL to CGI-58 is well documented, 3 and PNPLA3 148M also colocalizes with CGI-58. 4 CGI-58 is felt to decrease liver fat content by binding to and activating ATGL and hence by increasing lipolysis.…”

Section: Potential Mechanism Underlying the Pnpla3 I148m -Hepatic Stementioning

confidence: 97%

Potential mechanism underlying the PNPLA3I 148 M‐Hepatic steatosis connection

Yang

Mitchell

2015

Hepatology

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between sarcopenia and NAFLD may partially be related to low vitamin D status.The increase of an indoor lifestyle and aging society has brought deficiency of vitamin D in the general population. Traditionally, vitamin D has been regarded as a vital factor for bone health and calcium metabolism. Recently, deficiency of vitamin D has been known to be associated with chronic metabolic disorders, including type 2 diabetes, obesity, metabolic syndrome, and cardiovascular disease, beyond calcium and bone metabolism.Furthermore Potential Mechanism Underlying the PNPLA3 I148M -Hepatic Steatosis ConnectionTo the Editor:Smagris et al. 1 elegantly show that knock-in mice homozygous for the PNPLA3 148M variant of adiponutrin develop hepatic steatosis when fed a high-sucrose diet, reproducing the strongest known genetic association with hepatic steatosis in humans. PNPLA3 148M knock-in mice provide a powerful tool for exploring the mechanisms of hepatic steatosis.One plausible and testable mechanism involves the dynamic interactions among lipases and other lipid droplet (LD) surface proteins. Potentially, PNPLA3 148M may compete with ATGL (PNPLA2, the major hepatic triglyceride lipase) for CGI-58 binding (Fig. 1), leading to the reduced lipolytic capacity, steatosis and increase of large LDs observed in PNPLA3 148M knock-in livers.Several observations are consistent with this hypothesis. The investigators show that PNPLA3 148M accumulates on the LD surface in knock-in livers, in contrast to wild-type PNPLA3 148I , which is barely detectable on normal liver LDs. Therefore, ATGL and PNPLA3 148M are both present on the LD surface. Also, ATGL and PNPLA3 share the highest homology of any patatin domain proteins. 2 Binding of ATGL to CGI-58 is well documented, 3 and PNPLA3 148M also colocalizes with CGI-58. 4 CGI-58 is felt to decrease liver fat content by binding to and activating ATGL and hence by increasing lipolysis. Conversely, CGI-58 deficiency is known to produce hepatic steatosis. 5 Although Smagris et al. found that total CGI-58 levels did not correlate with severity of hepatic steatosis, competition for CGI-58 binding between ATGL and PNPLA3 148M may reduce the ATGL-bound fraction of CGI-58 in PNPLA3 148M knock-in livers, inhibiting lipolysis and resulting in hepatic steatosis.Although more-complex mechanisms may be responsible for PNPLA3 148M

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Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome

Cited by 791 publications

References 36 publications

The effect of inhibition of endoplasmic reticulum stress on lipolysis in white adipose tissue in a rat model of chronic kidney disease

The effect of inhibition of endoplasmic reticulum stress on lipolysis in white adipose tissue in a rat model of chronic kidney disease

Triacylglycerol Metabolism In Adipose Tissue

Potential mechanism underlying the PNPLA3I 148 M‐Hepatic steatosis connection

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