Apolipoprotein B and triacylglycerol secretion in human triacylglycerol hydrolase transgenic mice

Wei, Enhui; Alam, Mohammad Nurul; Sun, Fengcheng; Agellon, Luis B.; Vance, Dennis E.; Lehner, Richard

doi:10.1194/jlr.m700320-jlr200

Cited by 51 publications

(42 citation statements)

References 57 publications

(68 reference statements)

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“…To date, two potential ER-localized lipases have been identifi ed, AADA and TGH. While a positive role of TGH in hepatic VLDL assembly has been documented (14)(15)(16)(17)20 ), very little is known about the function of AADA. AADA was initially characterized through its drug transforming ability in vitro ( 27 ).…”

Section: Increased Fatty Acid Oxidation In Aada Expressing Cellsmentioning

confidence: 99%

“…These lipid droplets are believed to serve as lipid donors for bulk lipidation of primordial apoB-containing particles ( 10-13 ). One enzyme that has been implicated to play a role in the hydrolysis of stored TG pools and assembly of VLDL is an ER-associated triacylglycerol hydrolase (TGH) (14)(15)(16)(17)(18)(19)(20). Inhibition of TGH leads to decreased TG mobilization and apoB secretion from hepatocytes ( 15 ).…”

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confidence: 99%

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Arylacetamide deacetylase attenuates fatty-acid-induced triacylglycerol accumulation in rat hepatoma cells

Erickson

Thomason-Hughes

et al. 2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org endoplasmic reticulum (ER) lumenal lipid droplets ( 10-12 ). These lipid droplets are believed to serve as lipid donors for bulk lipidation of primordial apoB-containing particles ( 10-13 ). One enzyme that has been implicated to play a role in the hydrolysis of stored TG pools and assembly of VLDL is an ER-associated triacylglycerol hydrolase (TGH) (14)(15)(16)(17)(18)(19)(20). Inhibition of TGH leads to decreased TG mobilization and apoB secretion from hepatocytes ( 15 ). However, treatment of hepatocytes with a TGH-specifi c inhibitor reduced secretion of TG and apoB to a lesser extent than the general lipase inhibitor, diethyl p -nitrophenyl phosphate (E600), suggesting that other lipases may also contribute to VLDL assembly ( 15 ). The fact that perinatal rat hepatocytes are capable of TG secretion in the absence of TGH expression in this particular developmental stage provides further support for the existence of additional lipases ( 21,22 ).In addition to VLDL assembly, fatty acids released from intracellular stores can be utilized for energy production via ␤ -oxidation in the mitochondria. Unlike the well-described roles of adipose triglyceride lipase (ATGL) and hormonesensitive lipase (HSL) in the mobilization of TG stores in adipose tissue ( 23-26 ), the identity of hepatic lipases supporting ␤ -oxidation is still unclear. Arylacetamide deacetylase (AADA) shares sequence homology with HSL ( 27 ) and possesses a classical lipase/esterase GXSXG active site motif ( 27,28 ). Trickett et al. ( 28 ) have shown that hepatic AADA mRNA levels follow a diurnal rhythm with an identical pattern to hepatic VLDL secretion in mice. In this study, we Hydrolysis of hepatic intracellular triacylglycerol (TG) stores generates substrates for ␤ -oxidation and lipid resynthesis, some of which are utilized for the assembly of VLDLs ( 1-3 ). The assembly of VLDL involves both cotranslational and posttranslational addition of lipids to apolipoprotein B (apoB) ( 4-7 ). The transfer of lipids to nascent apoB particles is facilitated by the microsomal triglyceride transfer protein ( 8, 9 ). Microsomal triglyceride transfer protein is also responsible for the formation of apoB-free This work was supported by a Grant-in-Aid from the Heart and Stroke Foundation of Alberta, Northwest Territories, and Nunavut. V.L., B.E., and M.T.-H.

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Section: Increased Fatty Acid Oxidation In Aada Expressing Cellsmentioning

confidence: 99%

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confidence: 99%

Arylacetamide deacetylase attenuates fatty-acid-induced triacylglycerol accumulation in rat hepatoma cells

Erickson

Thomason-Hughes

et al. 2010

Journal of Lipid Research

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“…First-strand cDNA was synthesized from 2 ug total RNA using Superscript III reverse transcriptase (Invitrogen, CA, US) primed by oligo (dt) [12][13][14][15][16][17][18] and random primers (Invitrogen). Real-time qPCR was performed with the Platinum SYBR Green qPCR SuperMix-UDG kit (Invitrogen) in the Rotor-Gene 3000 instrument (Montreal Biotech, Quebec, CA) to detect the gene expression.…”

Section: Rna Isolation and Pcr Analysismentioning

confidence: 99%

“…[3][4][5][6] TG hydrolase (TGH), also termed carboxylesterase 3 (Ces3) or carboxylesterase Ces1d in mice and carboxylesterase 1 (CES1) in humans, has been shown to participate in the provision of substrates for VLDL assembly. [7][8][9][10][11][12][13] Overexpression of TGH in McArdle RH7777 cells augmented TG and ApoB100 secretion in the VLDL density range. 7 Liver-specific overexpression of human TGH in mice resulted in increased ApoB secretion and plasma TG concentration in vivo, 12 whereas inhibition of TGH activity decreased ApoB secretion both in vitro 8 and in vivo.…”

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confidence: 99%

Ces3/TGH Deficiency Improves Dyslipidemia and Reduces Atherosclerosis in Ldlr ^−/− Mice

Lian

Quiroga

et al. 2012

Circulation Research

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T he development of atherosclerosis and coronary heart disease is accelerated in patients with metabolic syndrome characterized by dyslipidemia and insulin resistance. Elevated circulating levels of apolipoprotein B (ApoB)-containing lipoproteins, such as low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL), are recognized independent risk factors for the development of atherosclerosis.1,2 Hepatic secretion of VLDL is one of the major determining factors of plasma ApoB concentration. The majority of VLVLtracylglycerol (TG) secreted from hepatocytes is derived from preformed stored TG through a process of lipolysis and reesterification.3-6 TG hydrolase (TGH), also termed carboxylesterase 3 (Ces3) or carboxylesterase Ces1d in mice and carboxylesterase 1 (CES1) in humans, has been shown to participate in the provision of substrates for VLDL assembly. 7-13Overexpression of TGH in McArdle RH7777 cells augmented TG and ApoB100 secretion in the VLDL density range. Liver-specific overexpression of human TGH in mice resulted in increased ApoB secretion and plasma TG concentration in vivo, 12 whereas inhibition of TGH activity decreased ApoB secretion both in vitro 8 and in vivo. 13 Furthermore, TGH knockout mice presented with reduced plasma lipids and improved insulin sensitivity and glucose homeostasis. 13The LDL receptor knockout (Ldlr) mouse is a well-established murine model for the study of atherosclerosis. The LDL receptor plays a major role in the clearance of atherogenic ApoB-containing lipoproteins from the circulation. Due to the prolonged plasma half-life of VLDL and LDL, after a high-fat, high-cholesterol diet, the Ldlr −/− mouse shows severe hyperlipidemia and dramatically elevated circulating atherogenic lipoproteins and consequently develops atherosclerotic lesions. [14][15][16] Objective: To investigate the contribution of TGH to atherosclerotic lesion development in mice that lack lowdensity lipoprotein receptor (LDLR). Methods and Results:

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“…In liver, TGH may mediate the lipolysis that precedes TG synthesis in very low-density lipoprotein formation. 64 …”

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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Apolipoprotein B and triacylglycerol secretion in human triacylglycerol hydrolase transgenic mice

Cited by 51 publications

References 57 publications

Arylacetamide deacetylase attenuates fatty-acid-induced triacylglycerol accumulation in rat hepatoma cells

Arylacetamide deacetylase attenuates fatty-acid-induced triacylglycerol accumulation in rat hepatoma cells

Ces3/TGH Deficiency Improves Dyslipidemia and Reduces Atherosclerosis in Ldlr ^−/− Mice

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

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Apolipoprotein B and triacylglycerol secretion in human triacylglycerol hydrolase transgenic mice

Cited by 51 publications

References 57 publications

Arylacetamide deacetylase attenuates fatty-acid-induced triacylglycerol accumulation in rat hepatoma cells

Arylacetamide deacetylase attenuates fatty-acid-induced triacylglycerol accumulation in rat hepatoma cells

Ces3/TGH Deficiency Improves Dyslipidemia and Reduces Atherosclerosis in Ldlr −/− Mice

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

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Ces3/TGH Deficiency Improves Dyslipidemia and Reduces Atherosclerosis in Ldlr ^−/− Mice