Evidence for the existence of isoenzymes of glycerol phosphate acyltransferase

Nimmo, Hugh G.

doi:10.1042/bj1770283

Cited by 37 publications

(26 citation statements)

References 28 publications

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“…Finding that GPAT4 localizes to LDs raised an apparent contradiction as members of the GPAT/AGPAT enzyme family had been reported as ER enzymes based on their cofractionation with microsomes (Aguado and Campbell, 1998; Coleman and Lee, 2004; Nimmo, 1979). To address this question, we localized GPAT4 and an ER marker (N-terminally GFP-tagged SEC61β).…”

Section: Resultsmentioning

confidence: 99%

Triacylglycerol Synthesis Enzymes Mediate Lipid Droplet Growth by Relocalizing from the ER to Lipid Droplets

et al. 2013

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SUMMARY Lipid droplets (LDs) store metabolic energy and membrane lipid precursors. With excess metabolic energy, cells synthesize triacylglycerol (TG) and form LDs that grow dramatically. It is unclear how TG synthesis relates to LD formation and growth. Here, we identify two LD subpopulations: smaller LDs of relatively constant size, and LDs that grow larger. The latter population contains isoenzymes for each step of TG synthesis. Glycerol-3-phosphate acyltransferase 4 (GPAT4), which catalyzes the first and rate-limiting step, relocalizes from the endoplasmic reticulum (ER) to a subset of forming LDs, where it becomes stably associated. ER-to-LD targeting of GPAT4 and other LD-localized TG synthesis isozymes is required for LD growth. Key features of GPAT4 ER-to-LD targeting and function in LD growth are conserved between Drosophila and mammalian cells. Our results explain how TG synthesis is coupled with LD growth and identify two distinct LD subpopulations based on their capacity for localized TG synthesis.

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Section: Resultsmentioning

confidence: 99%

Triacylglycerol Synthesis Enzymes Mediate Lipid Droplet Growth by Relocalizing from the ER to Lipid Droplets

et al. 2013

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“…It is remarkable, however, that the phenotypes of GPAT1 knock-out mice occur, even though ?60% of wild-type activity is provided by GPAT2 in the mitochondria. In adipose tissue and liver of normal rats, GPAT2 is likely only a minor component of total GPAT activity, since careful fractionation studies in these tissues have shown ,10% NEM-sensitive GPAT activity associated with mitochondria (27)(28)(29)(30). However, it is important to keep in mind that GPAT2 may contribute more significantly to total GPAT activity in other tissues and that measurement of NEM-sensitive GPAT activity in unfractionated tissues may assess mitochondrial GPAT2 in addition to microsomal GPAT isoforms.…”

Section: Mitochondrial Nem-sensitive Gpat (Gpat2)mentioning

confidence: 99%

“…These studies found that the mitochondrial isoform accounts for ?50% of total GPAT activity in rat liver and is significantly decreased upon fasting (27,28). The microsomal isoform is the major isoform in brown and white adipose tissue, accounting for 80-90% of total GPAT activity (29,30), and is dramatically upregulated during adipocyte differentiation (16,31,32).…”

Section: Tissue Distribution and Regulation Of Gpat Isoforms As Definmentioning

confidence: 99%

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

Gimeno¹,

Cao²

2008

Journal of Lipid Research

113

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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“…The distribution of GPAT isoforms varies greatly from tissue to tissue. In the liver, mitochondrial GPAT1 accounts for 50% of GPAT activity ( 39,40 ) whereas in heart, white adipose tissue, and brown adipose tissue, microsomal GPAT activity (GPAT 3 and 4) accounts for most of the activity ( 9,10,41,42 ). In contrast, in skeletal muscle, greater than 90% of GPAT activity is accounted for by GPAT1 ( 43 ).…”

Section: Activation Of Ppars Transactivates Gpat3 Gene Expressionmentioning

confidence: 97%

Expression and regulation of GPAT isoforms in cultured human keratinocytes and rodent epidermis

Lü

Jiang

Kim

et al. 2010

Journal of Lipid Research

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The principal function of the epidermis is to provide a protective barrier against transcutaneous water loss, which is essential for survival in a terrestrial environment. This permeability barrier is localized to the stratum corneum (SC), the outermost layer of the epidermis ( 1 ). This permeability barrier is mediated by extracellular lipids, primarily cholesterol, ceramides, and free fatty acids, which are delivered to the extracellular spaces of the SC by the secretion of lamellar body contents by differentiated keratinocytes ( 1 ). Lamellar bodies contain cholesterol, glucosylceramides, and phospholipids, and following lamellar body secretion the glucosylceramides are metabolized to ceramides, a process catalyzed by the enzyme ␤ -glucocerebrosidase, and the phospholipids are metabolized to free fatty acids, a reaction catalyzed by secretory phospholipases ( 1-4 ). The formation of lamellar bodies by keratinocytes requires the prior synthesis of suffi cient quantities of these three lipids in keratinocytes. Pertinently, disruption of the permeability barrier leads to a marked increase in epidermal cholesterol, ceramide, and fatty acid synthesis, which enhances the formation of lamellar bodies ( 1, 5 ). Conversely, inhibition of cholesterol, ceramides, or fatty acid synthesis in the epidermis impairs the formation of lamellar bodies, leading to the decreased delivery of lipid to the extracellular spaces of the SC and impaired permeability barrier function ( 6-8 ).Abstract Phospholipids are required for epidermal lamellar body formation. Glycerol 3-phosphate acyltransferases (GPATs) catalyze the initial step in the biosynthesis of glycerolipids. Little is known about the expression and regulation of GPATs in epidermis/keratinocytes. Here, we demonstrate that GPAT 1, 3, and 4 are expressed in epidermis/keratinocytes, whereas GPAT2 is not detected. In mouse epidermis, GPAT 3 and 4 are mainly localized to the upper layers whereas GPAT1 is found in both the upper and lower layers. GPAT1 and 3 mRNA increase during fetal rat epidermal development. No change in GPAT expression was observed in adult mice following acute permeability barrier disruption. Calcium-induced human keratinocyte differentiation increased GPAT3 mRNA whereas both GPAT1 and 4 mRNA levels decreased. In parallel, total GPAT activity increased 2-fold in differentiated keratinocytes attributable to an increase in N-ethylmaleimide (NEM) sensitive GPAT activity localized to microsomes with little change in NEM resistant activity, consistent with an increase in GPAT3. Furthermore, PPAR ␥ or PPAR ␦ activators increased GPAT3 mRNA, microsomal GPAT activity, and glycerol lipid synthesis without affecting the expression of GPAT1 or 4. Finally, both PPAR ␥ and PPAR ␦ activators increased GPAT3 mRNA via increasing its transcription. Thus, multiple isoforms of GPAT are expressed and differentially regulated in epidermis/keratinocytes. -Lu, B., Y. J. Jiang, P. Kim, A. Moser, P. M. Elias, C. Grunfeld, and K. R.

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Evidence for the existence of isoenzymes of glycerol phosphate acyltransferase

Cited by 37 publications

References 28 publications

Triacylglycerol Synthesis Enzymes Mediate Lipid Droplet Growth by Relocalizing from the ER to Lipid Droplets

Triacylglycerol Synthesis Enzymes Mediate Lipid Droplet Growth by Relocalizing from the ER to Lipid Droplets

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

Expression and regulation of GPAT isoforms in cultured human keratinocytes and rodent epidermis

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