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

Ruth E Gimeno,Jingsong Cao

doi:10.1194/jlr.r800013-jlr200

Abstract

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 sulfhydryl-modifying 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.

Highlights

Glycerol-3-phosphate acyltransferases (GPATs; EC2.3.1.15) catalyze the first step in the de novo synthesis of neutral lipids and glycerophospholipids
Glycerol-3-phosphate acyltransferases (GPATs; EC2.3.1.15) use glycerol-3-phosphate and fatty acyl-CoA as substrates to catalyze the formation of lysophosphatidic acid, a precursor for phosphatidic acid, which in turn is required for the biosynthesis of both triglycerides and glycerophospholipids (Fig. 1)
It has since been shown that GPAT activity is present in most organisms examined, including vertebrates, invertebrates, plants, fungi, and some bacteria [2]. [It should be noted that many bacterial species utilize the PlsX/Y pathway, which generates lysophosphatidic acid using acyl-phosphate, rather than acyl-CoA or acyl carrier protein, as a substrate [3]]

Summary

Resistant Sensitive Sensitive Sensitive

NM_020918 (h) NM_008149 (m) NM_017274 (r) NM_207328 (h) NM_001081089 (m) XM_238283 (r) NM_032717 (h) NM_172715 (m) NM_001025670 (r) NM_178819 (h) NM_018743 (m) NM_001047849 (r). Hepatic diacylglycerol and lysophosphatidic acid content are increased, and protein kinase e is activated in GPAT1 overexpressing rats, possibly explaining the insulin resistance in these animals [63] These parameters are decreased in GPAT1 knock-out mice fed a high-fat safflower diet, which may account for their insulin sensitivity, despite high fatty acyl-CoA levels [62]. GPAT1 knock-out mice have been reported to have increased oxidative stress in the liver, including increased reactive oxygen species (possibly secondary to increased b-oxidation), increased mitochondrial lipid peroxidation, decreased glutathione-S-transferase levels, and increased hepatocellular apoptosis and proliferation [67] This increase in oxidative stress, which is observed even in animals fed a low-fat diet, may contribute to the development of insulin resistance in GPAT1 knockout mice. Given the challenges in predicting membrane domains for integral membrane proteins, it is important to keep in mind, that these predictions need to be confirmed experimentally

ENZYMATIC ACTIVITY OF MAMMALIAN GPAT ISOFORMS

Findings

WHY SO MANY GPATs?