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

Autor:	Agarwal AK; Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390., Tunison K; Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390., Dalal JS; Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390., Nagamma SS; Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390., Hamra FK; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390., Sankella S; Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390., Shao X; Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390., Auchus RJ; Department of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390., Garg A; Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Jazyk:	angličtina
Zdroj:	Endocrinology [Endocrinology] 2017 Nov 01; Vol. 158 (11), pp. 3954-3973.
DOI:	10.1210/en.2017-00511
Abstrakt:	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 O-acyltransferase (AGPAT) enzymes transfer a fatty acid to the sn-2 carbon of sn-1-acylglycerol-3-phosphate (lysophosphatidic acid) 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 that 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 further explore the physiology of AGPAT1, we characterized a loss-of-function mouse model (Agpat1-/-). The majority of Agpat1-/- mice died before weaning and had low body weight and low plasma glucose levels, independent of plasma insulin and glucagon levels, with reduced percentage of body fat but not generalized lipodystrophy. These mice also had decreased hepatic messenger RNA expression of Igf-1 and Foxo1, suggesting a decrease in gluconeogenesis. In male mice, sperm development was impaired, with a late meiotic arrest near the onset of round spermatid production, and gonadotropins were elevated. Female mice showed oligoanovulation yet retained responsiveness to gonadotropins. Agpat1-/- mice also demonstrated abnormal hippocampal neuron development and developed audiogenic seizures. In summary, Agpat1-/- mice developed widespread disturbances of metabolism, sperm development, and neurologic function resulting 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 in which to study the contribution of phospholipid and triacylglycerol synthesis to physiology and diseases. (Copyright © 2017 Endocrine Society.)
Databáze:	MEDLINE
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