The role of mitochondrial glycerol-3-phosphate acyltransferase-1 in regulating lipid and glucose homeostasis in high-fat diet fed mice

Yazdi, Misak; Ahnmark, Andrea; William-Olsson, Lena; Snaith, Michael; Turner, Nigel; Osla, Fredrik; Wedin, Marianne; Asztély, Anna-Karin; Elmgren, Anders; Bohlooly‐Y, Mohammad; Schreyer, Sandra A.; Lindén, Daniel

doi:10.1016/j.bbrc.2008.02.156

Cited by 23 publications

(24 citation statements)

References 17 publications

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“…Similarly, in vivo, GPAT1 overexpression leads to decreased hepatic fatty acid oxidation and increased triglyceride biosynthesis (64). In GPAT1 knock-out mice, hepatic fatty acid oxidation rates and serum ketone bodies are increased (60,61), consistent with a preferential utilization of fatty acids through b-oxidation. Interestingly, however, the substrate of GPAT1, fatty-acyl-CoAs, are also increased in the livers of GPAT1 knock-out mice (60,62), suggesting that not all fatty-acyl-CoA can be utilized efficiently in the b-oxidation pathway in the absence of GPAT1.…”

Section: Mitochondrial Nem-resistant Gpat (Gpat1)mentioning

confidence: 93%

“…Although initial studies suggested decreased body weight in female GPAT1 knock-out mice (48), subsequent experiments showed that GPAT1 deletion did not protect mice from weight gain on a high fat diet (61,62). Similarly, adenoviral knock-down of GPAT1 in genetically obese ob/ob mice did not decrease their body weight (65).…”

Section: Mitochondrial Nem-resistant Gpat (Gpat1)mentioning

confidence: 99%

“…In GPAT1 knock-out mice, liver triglycerides and VLDL secretion as well as plasma triglycerides and cholesterol are decreased (48,(60)(61)(62), while rats (63) or mice (64) overexpressing GPAT1 in the liver have increased hepatic and serum triglycerides and increased triglyceride secretion. Adenoviral knock-down of GPAT1 in genetically obese ob/ob mice similarly decreased liver triglycerides but had no effect on plasma triglycerides (65).…”

Section: Mitochondrial Nem-resistant Gpat (Gpat1)mentioning

confidence: 99%

“…Interestingly, however, the substrate of GPAT1, fatty-acyl-CoAs, are also increased in the livers of GPAT1 knock-out mice (60,62), suggesting that not all fatty-acyl-CoA can be utilized efficiently in the b-oxidation pathway in the absence of GPAT1. It is noteworthy that the phenotypes of GPAT1 knock-out mice are more pronounced in females compared with males, suggesting a possible gender difference in GPAT1 action (48,61).…”

Section: Mitochondrial Nem-resistant Gpat (Gpat1)mentioning

confidence: 99%

“…GPAT1 knock-out mice fed a normal diet did not show any difference in insulin sensitivity (48). Insulin resistance was increased in GPAT1 knock-out mice compared with wild-type controls, when mice were fed either a high-fat, high-sucrose diet (60), or a diet high in coconut oil (61), but decreased, when mice were fed a high-fat diet rich in safflower oil (62). The decrease in insulin resistance on the high-fat diet rich in safflower oil occurred despite an increase in total hepatic fatty acyl-CoA (62).…”

Section: Mitochondrial Nem-resistant Gpat (Gpat1)mentioning

confidence: 99%

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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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Section: Mitochondrial Nem-resistant Gpat (Gpat1)mentioning

confidence: 93%

Section: Mitochondrial Nem-resistant Gpat (Gpat1)mentioning

confidence: 99%

Section: Mitochondrial Nem-resistant Gpat (Gpat1)mentioning

confidence: 99%

Section: Mitochondrial Nem-resistant Gpat (Gpat1)mentioning

confidence: 99%

Section: Mitochondrial Nem-resistant Gpat (Gpat1)mentioning

confidence: 99%

See 3 more Smart Citations

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

Gimeno¹,

Cao²

2008

Journal of Lipid Research

114

100

View full text Add to dashboard Cite

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Lipid oversupply, selective insulin resistance, and lipotoxicity: Molecular mechanisms

Chavez

Summers

2010

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

153

106

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The accumulation of fat in tissues not suited for lipid storage has deleterious consequences on organ function, leading to cellular damage that underlies diabetes, heart disease, and hypertension. To combat these lipotoxic events, several therapeutics improve insulin sensitivity and/or ameliorate features of metabolic disease by limiting the inappropriate deposition of fat in peripheral tissues (i.e. thiazolidinediones, metformin, and statins). Recent advances in genomics and lipidomics have accelerated progress towards understanding the pathogenic events associated with the excessive production, underutilization, or inefficient storage of fat. Herein we review studies applying pharmacological or genetic strategies to manipulate the expression or activity of enzymes controlling lipid deposition, in order to gain a clearer understanding of the molecular mechanisms by which fatty acids contribute to metabolic disease.

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How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

Wang

Airola

Reue

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Triacylglycerols (TAG) serve as the predominant form of energy storage in mammalian cells, and TAG synthesis influences conditions such as obesity, fatty liver, and insulin resistance. In most tissues, the glycerol 3-phosphate pathway enzymes are responsible for TAG synthesis, and the regulation and function of these enzymes is therefore important for metabolic homeostasis. Here we review the sites and regulation of glycerol-3-phosphate acyltransferase (GPAT), acylglycerol-3-phosphate acyltransferase (AGPAT), lipin/phosphatidic acid phosphatase (PAP), and diacylglycerol acyltransferase (DGAT) enzyme action. We highlight the critical roles that these enzymes play in human health by reviewing Mendelian disorders that result from mutation in the corresponding genes. We also summarize the valuable insights that genetically engineered mouse models have provided into the cellular and physiological roles of GPATs, AGPATs, lipins and DGATs. Finally, we comment on the status and feasibility of therapeutic approaches to metabolic disease that target enzymes of the glycerol 3-phosphate pathway.

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The role of mitochondrial glycerol-3-phosphate acyltransferase-1 in regulating lipid and glucose homeostasis in high-fat diet fed mice

Cited by 23 publications

References 17 publications

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

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

Lipid oversupply, selective insulin resistance, and lipotoxicity: Molecular mechanisms

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

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