Attenuation of Adipocyte Triacylglycerol Hydrolase Activity Decreases Basal Fatty Acid Efflux

Wei, Enhui; Gao, Wenhui; Lehner, Richard

doi:10.1074/jbc.m605789200

Cited by 50 publications

(49 citation statements)

References 46 publications

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“…Human ATGL resides, in part, in the ER ( 51 ) and has signifi cant TG hydrolysis activity independent of its translocation to lipid droplets where it interacts with its activator, CGI-58 ( 52 ). However, microsomes also contain other TG lipases, such as CES3/TGH ( 53 ). The lipase responsible for the increased lipolytic activity of microsomes from CETP-defi cient cells remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Defective triglyceride biosynthesis in CETP-deficient SW872 cells

Greene

Izem

Morton

2015

Journal of Lipid Research

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with adipose tissue CETP mRNA levels in both man and hamster ( 6,7 ), showing the importance of this tissue in both lipid storage and the modulation of intravascular lipid metabolism.While most CETP is secreted by cells, a portion is retained ( 8-10 ). Much of the intracellular CETP pool is associated with the endoplasmic reticulum (ER), with increased concentrations near lipid droplets ( 8,11 ). Both cytoplasmic and lipid-droplet pools of CETP have been observed as well ( 11 ). Although the mechanism for CETP release into the cytoplasm is unknown, the escape of other ER luminal proteins to the cytoplasm has been reported (12)(13)(14).In addition to its role in plasma lipoprotein metabolism, multiple studies suggest that CETP has other functions. Cell-associated CETP promotes CE uptake from HDL, stimulates the cell's ability to effl ux cholesterol, and infl uences the storage of CE in cells (15)(16)(17)(18)(19). In addition to altering cellular cholesterol metabolism, both overexpression and under-expression of CETP in SW872 cells, a human cell line commonly used as an adipocyte model, reduce the capacity of these cells to store TG ( 10, 11 ). A role for CETP in adipocyte lipid storage is further supported by observations in transgenic mice. Adipose tissue-specifi c expression of human CETP in mice results in smaller adipocytes containing less TG and cholesterol, and signifi cantly reduces the expression of key lipogenic genes ( 20 ). In hypertriglyceridemic mice, CETP expression normalizes subcutaneous adipose depots and visceral adipocyte size ( 21 ). And in humans, a CETP gene variant that affects the coding sequence of CETP is associated with increased adiposity following long-term overfeeding ( 22 ).In this study, we have examined pathways involved in TG homeostasis in order to understand the metabolic Abstract We previously reported that reducing the expression of cholesteryl ester transfer protein (CETP) disrupts cholesterol homeostasis in SW872 cells and causes an ‫ف‬ 50% reduction in TG. The causes of this reduced TG content, investigated here, could not be attributed to changes in the differentiation status of CETP-defi cient cells, nor was there evidence of endoplasmic reticulum (ER) stress. In short-term studies, the total fl ux of oleate through the TG biosynthetic pathway was not altered in CETP-defi cient cells, although mRNA levels of some pathway enzymes were different. However, the conversion of diglyceride (DG) to TG was impaired. In longer-term studies, newly synthesized TG was not effectively transported to lipid droplets, yet this lipid did not accumulate in the ER, apparently due to elevated lipase activity in this organelle. DG, shown to be a novel CETP substrate, was also ineffi ciently transferred to lipid droplets. This may reduce TG synthesis on droplets by resident diacylglycerol acyltransferase. Overall, these data suggest that the decreased TG content of CETP-defi cient cells arises from the reduced conversion of DG to TG in the ER and/or on the lipid droplet surface, and enhanced ...

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Section: Discussionmentioning

confidence: 99%

Defective triglyceride biosynthesis in CETP-deficient SW872 cells

Greene

Izem

Morton

2015

Journal of Lipid Research

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“…However, it is not known if adiponutrin and GS2 are actually TG hydrolases. An additional lipase, TG hydrolase or carboxylesterase-3, has been identified in rat adipose tissue (28,29). Although the hydrolysis of TG is catalyzed by all these lipases, HSL can hydrolyze both TG and DAG, the latter being a better substrate (30).…”

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confidence: 99%

Adipose Triglyceride Lipase Is Implicated in Fuel- and Non-fuel-stimulated Insulin Secretion

Peyot

Guay

Latour

et al. 2009

Journal of Biological Chemistry

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Free fatty acids (FFA)5 and other lipid molecules are important for proper glucose-stimulated insulin secretion (GSIS) by ␤-cells. Thus, deprivation of fatty acids (FA) in vivo (1) diminishes GSIS, whereas a short term exposure to FFA enhances it (1-3). In contrast, a sustained provision of FA, particularly in the presence of high glucose in vitro, is detrimental to ␤-cells in that it reduces insulin gene expression (4) and secretion (5) and induces ␤-cell apoptosis (6). The FA supply to the ␤-cells can be from exogenous sources, such as plasma FFAs and lipoproteins, or endogenous sources, such as intracellular triglyceride (TG) stores. Studies from our laboratory (7-10) and others (11,12) support the concept that the hydrolysis of endogenous TG plays an important role in fuel-induced insulin secretion because TG depletion with leptin (13) or inhibition of TG lipolysis by lipase inhibitors such as 3,5-dimethylpyrazole (7) or orlistat (11, 12) markedly curtail GSIS in rat islets. Furthermore, mice with ␤-cell-specific knock-out of hormone-sensitive lipase (HSL), which hydrolyzes both TG and diacylglycerol (DAG), show defective first phase GSIS in vivo and in vitro (14).Lipolysis is an integral part of an essential metabolic pathway, the TG/FFA cycle, in which FFA esterification onto a glycerol backbone leading to the synthesis of TG is followed by its hydrolysis with the release of the FFA that can then be re-esterified.

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“…60 Knockdown of TGH in NIH-3T3 cells reduces basal lipolysis. 61 A paralog of TGH in mice, TGH-2, stimulates lipolysis if overexpressed in NIH-3T3 cells, and its knockdown diminishes lipolysis. 62 TGH can catalyze a variety of FA ester cleavage or synthesis, or FA transfer reactions, 63 and its role in adipocyte lipolysis remains unproven.…”

Section: Control Of Lipolysismentioning

confidence: 99%

Genetics, physiology and perinatal influences in childhood obesity: view from the Chair

Mitchell

2009

Int J Obes

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The current epidemic of childhood obesity will be a serious threat to population health for at least the next several decades. The biology of childhood obesity was the theme of an international symposium held in November 2007. Speakers discussed monogenic causes of obesity, prenatal epigenetic programing, neurobehavioral aspects of obesity, and hormonal and neuroendocrine abnormalities, and the insights provided by non-murine models for understanding the biology of early-onset obesity. Several new developments have been reported in white and brown adipose tissue biology. They are summarized briefly in this review and include observations about cell lineage of adipocytes, the renewal of adipocytes throughout life and the numerous factors that influence adipocyte fatty acid release. The biological underpinnings of childhood obesity are multiple and complex.

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Attenuation of Adipocyte Triacylglycerol Hydrolase Activity Decreases Basal Fatty Acid Efflux

Cited by 50 publications

References 46 publications

Defective triglyceride biosynthesis in CETP-deficient SW872 cells

Defective triglyceride biosynthesis in CETP-deficient SW872 cells

Adipose Triglyceride Lipase Is Implicated in Fuel- and Non-fuel-stimulated Insulin Secretion

Genetics, physiology and perinatal influences in childhood obesity: view from the Chair

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