3 years ago

Metabolic, Reproductive, and Neurologic Abnormalities in Agpat1-Null Mice.

Garg, Agarwal, Auchus, Tunison, Dalal, Shao, Sankella, Hamra, Nagamma
Defects in the biosynthesis of phospholipids and neutral lipids are associated with cell membrane dysfunction, disrupted energy metabolism, and diseases including lipodystrophy. In these pathways, the 1-acylglycerol-3-phosphate acyltransferase (AGPAT) enzymes transfer a fatty acid to the sn-2 carbon of sn-1-acylglycerol-3-phosphate (lysophosphatidic acid/LPA) to form sn-1, 2-acylglycerol-3-phosphate (phosphatidic acid/PA). PA is a precursor for key phospholipids and diacylglycerol. AGPAT1 and AGPAT2 are highly homologous isoenzymes and are both expressed in adipocytes. Genetic defects in AGPAT2 cause congenital generalized lipodystrophy, indicating that AGPAT1 cannot compensate for loss of AGPAT2 in adipocytes. To explore further the physiology of AGPAT1, we characterized a loss-of-function mouse model (Agpat1-/-). The majority of Agpat1-/- mice die before weaning and have low body weight and low plasma glucose, independent of plasma insulin and glucagon levels, with reduced percent body fat but not generalized lipodystrophy. These mice also have decreased hepatic mRNA expression of Igf-1 and Foxo1, suggesting a decrease in gluconeogenesis. In male mice, sperm development is impaired, with a late meiotic arrest near the onset of round spermatid production, and gonadotropins are elevated. Female mice show oligoanovulation, yet retain responsiveness to gonadotropins. Agpat1-/- mice also demonstrate abnormal hippocampal neuron development and develop audiogenic seizures. In summary, Agpat1-/- mice develop widespread disturbances of metabolism, sperm development, and neurologic function resultant from disrupted phospholipid homeostasis. AGPAT1 appears to serve important functions in the physiology of multiple organ-systems. The Agpat1-deficient mouse provides an important model to study the contribution of phospholipid and triglyceride synthesis to physiology and diseases.

Publisher URL: http://doi.org/10.1210/en.2017-00511

DOI: 10.1210/en.2017-00511

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