Mice deleted for GPAT3 have reduced GPAT activity in white adipose tissue and altered energy and cholesterol homeostasis in diet-induced obesity
Mice deleted for GPAT3 have reduced GPAT activity in white adipose tissue and altered energy and cholesterol homeostasis in diet-induced obesity
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DOI：
10.1152/ajpendo.00666.2013
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发表时间：
2014-05-01
影响因子：
5.1
通讯作者：
Gimeno, Ruth E.
中科院分区：
文献类型：
--
作者：
Cao, Jingsong;Perez, Sylvie;Gimeno, Ruth E.
3-磷酸甘油酰基转移酶 (GPAT) 催化甘油脂和甘油磷脂合成的第一步。微粒体 GPAT 是主要的 GPAT 活性，由至少两个密切相关的基因 GPAT3 和 GPAT4 编码。为了研究 GPAT3 的体内功能，我们生成了 Gpat3 缺陷型 (Gpat3(-/-)) 小鼠。 Gpat3(-/-)小鼠白色脂肪组织中的总GPAT活性降低了80%，表明GPAT3是该组织中主要的GPAT。在肝脏中，GPAT3 缺失对总 GPAT 活性没有影响，但导致 N-乙基马来酰亚胺敏感的 GPAT 活性降低 30%。 Gpat3(-/-) 小鼠能够存活且具有生育能力，并且在标准实验室食物中没有表现出明显的代谢异常。然而，当喂食高脂肪饮食时，雌性 Gpat3(-/-) 小鼠体重增加和肥胖减少，能量消耗增加。在雄性 Gpat3(-/-) 小鼠中也观察到能量消耗增加，但并未伴随体重的显着变化。 GPAT3 缺乏会降低进食后的血糖水平，但不会降低空腹的血糖水平，并且往往会改善饮食诱导的肥胖雄性和雌性小鼠的葡萄糖耐量。在高脂肪饮食下，Gpat3(-/-) 小鼠的肝脏增大，并表现出胆固醇代谢失调。这些数据表明 GPAT3 是白色脂肪组织中的主要 GPAT，并揭示了该酶在调节能量、葡萄糖和脂质稳态中的重要作用。
Glycerol-3-phosphate acyltransferases (GPATs) catalyze the first step in the synthesis of glycerolipids and glycerophospholipids. Microsomal GPAT, the major GPAT activity, is encoded by at least two closely related genes, GPAT3 and GPAT4. To investigate the in vivo functions of GPAT3, we generated Gpat3-deficient (Gpat3(-/-)) mice. Total GPAT activity in white adipose tissue of Gpat3(-/-) mice was reduced by 80%, suggesting that GPAT3 is the predominant GPAT in this tissue. In liver, GPAT3 deletion had no impact on total GPAT activity but resulted in a 30% reduction in N-ethylmaleimide-sensitive GPAT activity. The Gpat3(-/-) mice were viable and fertile and exhibited no obvious metabolic abnormalities on standard laboratory chow. However, when fed a high-fat diet, female Gpat3(-/-) mice showed decreased body weight gain and adiposity and increased energy expenditure. Increased energy expenditure was also observed in male Gpat3(-/-) mice, although it was not accompanied by a significant change in body weight. GPAT3 deficiency lowered fed, but not fasted, glucose levels and tended to improve glucose tolerance in diet-induced obese male and female mice. On a high-fat diet, Gpat3(-/-) mice had enlarged livers and displayed a dysregulation in cholesterol metabolism. These data establish GPAT3 as the primary GPAT in white adipose tissue and reveal an important role of the enzyme in regulating energy, glucose, and lipid homeostasis.