Agpat6 deficiency causes subdermal lipodystrophy and resistance to obesity

Vergnes, Laurent; Beigneux, Anne P.; Davis, Ryan M.; Watkins, Steven M.; Young, Stephen G.; Reue, Karen

doi:10.1194/jlr.m500553-jlr200

Cited by 112 publications

(145 citation statements)

References 32 publications

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“…The discovery of these AGPAT2 mutations suggested an important physiological function for these enzymes in TAG synthesis. Recent findings in AGPAT6-null mice further support this role [29]. AGPAT6 is normally expressed at high levels in WAT, brown adipose tissue and liver.…”

Section: Biosynthesis Of Triacylglycerolmentioning

confidence: 64%

“…To date, eight AGPAT genes have been identified, although the physiological functions of each are not well established [28,29]. Mutations in AGPAT2, the major isoform in adipose tissue, have been reported in patients with congenital generalized lipodystrophy, a rare autosomal recessive disorder characterized by a marked lack of body fat since birth [3].…”

Section: Biosynthesis Of Triacylglycerolmentioning

confidence: 99%

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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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Section: Biosynthesis Of Triacylglycerolmentioning

confidence: 64%

Section: Biosynthesis Of Triacylglycerolmentioning

confidence: 99%

Triacylglycerol Metabolism In Adipose Tissue

et al. 2007

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“…A deficiency of AGPAT6 in mice results in resistance to dietinduced and genetic forms of obesity. Brown fat mass was significantly reduced, and DG and TG levels in milk and subdermal fat were reduced by nearly 90% (20,21). These studies suggest that AGPAT6 has a significant role in lipid biosynthesis.…”

mentioning

confidence: 59%

AGPAT6 Is a Novel Microsomal Glycerol-3-phosphate Acyltransferase

Chen

Kuo

et al. 2008

Journal of Biological Chemistry

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128

141

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AGPAT6 is a member of the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) family that appears to be important in triglyceride biosynthesis in several tissues, but the precise biochemical function of the enzyme is unknown. In the current study, we show that AGPAT6 is a microsomal glycerol-3-phosphate acyltransferase (GPAT). Membranes from HEK293 cells overexpressing human AGPAT6 had higher levels of GPAT activity. Substrate specificity studies suggested that AGPAT6 was active against both saturated and unsaturated long-chain fatty acyl-CoAs. Both glycerol 3-phosphate and fatty acyl-CoA increased the GPAT activity, and the activity was sensitive to N-ethylmaleimide, a sulfhydryl-modifying reagent. Purified AGPAT6 protein possessed GPAT activity but not AGPAT activity. Using [ 13 C 7 ]oleic acid labeling and mass spectrometry, we found that overexpression of AGPAT6 increased both lysophosphatidic acid and phosphatidic acid levels in cells. In these studies, total triglyceride and phosphatidylcholine levels were not significantly altered, although there were significant changes in the abundance of specific phosphatidylcholine species. Human AGPAT6 is localized to endoplasmic reticulum and is broadly distributed in tissues. Membranes of mammary epithelial cells from Agpat6-deficient mice exhibited markedly reduced GPAT activity compared with membranes from wildtype mice. Reducing AGPAT6 expression in HEK293 cells through small interfering RNA knockdown suggested that AGPAT6 significantly contributed to HEK293 cellular GPAT activity. Our data indicate that AGPAT6 is a microsomal GPAT, and we propose renaming this enzyme GPAT4.

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“…Like GPAT3, GPAT4 is widely expressed and can be detected at the mRNA level in most tissues examined (72)(73)(74). Mouse GPAT4 is most highly expressed in brown adipose tissue, white adipose tissue, and liver, but is also present at high levels in the testis and in different parts of the brain (73,74).…”

Section: Microsomal Nem-sensitive Gpat4 (Gpat4)mentioning

confidence: 99%

Thematic Review Series: Glycerolipids. Mammalian glycerol-3-phosphate acyltransferases: new genes for an old activity

Gimeno¹,

Cao²

2008

Journal of Lipid Research

114

100

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Glycerol-3-phosphate acyltransferases (GPATs; EC2.3.1.15) catalyze the first step in the de novo synthesis of neutral lipids (triglycerides) and glycerophospholipids. The existence of multiple enzyme isoforms with GPAT activity was predicted many years ago when GPAT activities with distinct kinetic profiles and sensitivity to inhibitors were characterized in two subcellular compartments, mitochondria and microsomes. We now know that mammals have at least four GPAT isoforms with distinct tissue distribution and function. GPAT1 is the major mitochondrial GPAT isoform and is characterized by its resistance to sulfhydrylmodifying reagents, such as N-ethylmaleimide (NEM). GPAT2 is a minor NEM-sensitive mitochondrial isoform. The activity referred to as microsomal GPAT is encoded by two closely related genes, GPAT3 and GPAT4. GPAT isoforms are important regulators of cellular triglyceride and phospholipid content, and may channel fatty acids toward particular metabolic fates. Overexpression and knock-out studies suggest that GPAT isoforms can play important roles in the development of hepatic steatosis, insulin resistance, and obesity; GPAT isoforms are also important for lactation. This review summarizes the current state of knowledge on mammalian GPAT isoforms.-Gimeno, R. E., and J. Cao. Mammalian glycerol-3-phosphate acyltransferases: new genes for an old activity.

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Agpat6 deficiency causes subdermal lipodystrophy and resistance to obesity

Cited by 112 publications

References 32 publications

Triacylglycerol Metabolism In Adipose Tissue

Triacylglycerol Metabolism In Adipose Tissue

AGPAT6 Is a Novel Microsomal Glycerol-3-phosphate Acyltransferase

Thematic Review Series: Glycerolipids. Mammalian glycerol-3-phosphate acyltransferases: new genes for an old activity

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