Abstract
Acyl-CoA:glycerol-sn-3-phosphate acyltransferase (GPAT) is an enzyme responsible for the rate-limiting step in the synthesis of glycerophospholipids and triacylglycerol (TAG). The enzymes of mammalian species are classified into four isoforms; GPAT1 and GPAT2 are localized in the mitochondrial outer membrane, whereas GPAT3 and GPAT4 are localized in the endoplasmic reticulum membrane. The activity of each enzyme expressed is associated with physiological and pathological functions. The transcriptional regulation is well known, particularly in GPAT1. GPAT1 mRNA expression is mainly regulated by the binding of the transcriptional factor SREBP-1c to the specific element (the sterol regulatory element) flanking the GPAT1 promoter. The TAG level is controlled by the insulin-induced transcriptional expression of GPAT1, which occupies most of the GPAT activity in the liver. The transcriptional regulation of the other three GPAT isoforms remains undetermined in detail. It is predicted that retinoic acid serves as a transcription factor in the GPAT2 promoter. PPARγ (peroxisome proliferator-activated receptor γ) increases the mRNA expression of GPAT3, which is associated with TAG synthesis in adipose tissues. Although GPAT has been considered to be a key enzyme in the production of TAG, unexpected functions have recently been reported, particularly in GPAT2. It is likely that GPAT2 is associated with tumorigenesis and normal spermatogenesis. In this review, the physiological and pathophysiological roles of the four GPAT isoforms are described, alongside the transcriptional regulation of these enzymes.
Highlights
The acylation of glycerol-3-phosphate (G3P) is the first step, as well as the rate-limiting step, in the synthesis of glycerophospholipids and triacylglycerol (TAG)
The improvement of insulin resistance is expected in ob/ob mice lacking GPAT1, the GPAT1 deficiency in ob/ob mice diminishes hepatic steatosis but does not protect against insulin resistance [57]. These results suggest that decreased hepatic steatosis alone does not improve insulin resistance and that a mechanism other than the DAG-induced protein kinase Ce (PKCe) activation contributes to insulin resistance in ob/ob mice
The dramatic elevation of TAG synthesis in fasting/refeeding is nowadays explained by transcriptional regulation of GPAT1, which is first identified in DNA and at a protein level
Summary
The acylation of glycerol-3-phosphate (G3P) is the first step, as well as the rate-limiting step, in the synthesis of glycerophospholipids and triacylglycerol (TAG). The enzyme which catalyzes this reaction is designated acyl-CoA:glycerol-sn-3-phosphate acyltransferase (GPAT) (EC 2.3.1.15). In the glycerol phosphate pathway, G3P is acylated by GPAT to form LPA (1-acyl-G3P, abbreviated to AGP). DAG is esterified by DAG acyltransferase (DGAT) to form TAG In this glycerol phosphate pathway, the GPAT is the rate-limiting enzyme because it shows the lowest specific activity among the enzymes involved in TAG synthesis [1]. Sci. 2019, 20, 964 pathophysiological functions are described in this review In addition to the regulatory mechanism of these enzymes, their physiological and pathophysiological functions are described in this review
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