Genetically altered expression of spermidine/spermine N1-acetyltransferase affects fat metabolism in mice via acetyl-CoA
Genetically altered expression of spermidine/spermine N1-acetyltransferase affects fat metabolism in mice via acetyl-CoA
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DOI：
10.1074/jbc.m610265200
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发表时间：
2007-03-16
影响因子：
4.8
通讯作者：
Porter, Carl W.
中科院分区：
文献类型：
--
作者：
Jell, Jason;Merali, Salim;Porter, Carl W.
乙酰化酶，亚精胺/精胺N-1-乙酰转移酶，通过调节多胺输出和催化参与多胺稳态。以前，我们报道过，在培养的肿瘤细胞和小鼠中的酶的过表达激活代谢通量通过多胺途径和耗尽N-1-乙酰转移酶辅酶和脂肪酸前体，乙酰辅酶A。在这里，我们研究了这种可能性，在亚精胺/精胺N-1-乙酰转移酶转基因小鼠中的酶是全身过表达和亚精胺/精胺N（-）（1）乙酰转移酶基因敲除小鼠。前者的组织的特点是N-1-乙酰转移酶活性增加，组织和尿乙酰化多胺的显着升高，多胺生物合成酶活性的补偿性增加，通过多胺途径的代谢通量增加。这些多胺的影响伴随着减少白色脂肪乙酰-和丙二酰-CoA池，一个主要的（20倍）增加葡萄糖和棕榈酸氧化，和一个明显的瘦表型。在SSAT-ko小鼠中，观察到多胺与脂肪代谢的相反关系。在没有N-1-乙酰化的多胺，有一个转变，尿和组织多胺的代谢通量下降的指示。这伴随着白色脂肪乙酰辅酶A和丙二酰辅酶A池的增加，脂肪棕榈酸和葡萄糖氧化的减少，以及体脂的积累。后者在高脂肪饮食下进一步放大，基因敲除小鼠的体重增加了野生型小鼠的两倍。提出了一种模型，其中亚精胺/精胺N-1-乙酰转移酶的表达状态通过代谢调节组织乙酰和丙二酰辅酶A水平来改变体脂积累，从而影响脂肪酸的生物合成和氧化。
The acetylating enzyme, spermidine/spermine N-1-acetyltransferase, participates in polyamine homeostasis by regulating polyamine export and catabolism. Previously, we reported that overexpression of the enzyme in cultured tumor cells and mice activates metabolic flux through the polyamine pathway and depletes the N-1-acetyltransferase coenzyme and fatty acid precursor, acetyl-CoA. Here, we investigate this possibility in spermidine/spermine N-1-acetyltransferase transgenic mice in which the enzyme is systemically overexpressed and in spermidine/spermine N(-)(1)acetyltransferase knock-out mice. Tissues of the former were characterized by increased N-1-acetyltransferase activity, a marked elevation in tissue and urinary acetylated polyamines, a compensatory increase in polyamine biosynthetic enzyme activity, and an increase in metabolic flux through the polyamine pathway. These polyamine effects were accompanied by a decrease in white adipose acetyl- and malonyl-CoA pools, a major (20-fold) increase in glucose and palmitate oxidation, and a distinctly lean phenotype. In SSAT-ko mice, the opposite relationship between polyamine and fat metabolism was observed. In the absence of N-1-acetylation of polyamines, there was a shift in urinary and tissue polyamines indicative of a decline in metabolic flux. This was accompanied by an increase in white adipose acetyl- and malonyl-CoA pools, a decrease in adipose palmitate and glucose oxidation, and an accumulation of body fat. The latter was further exaggerated under a high fat diet, where knock-out mice gained twice as much weight as wild-type mice. A model is proposed whereby the expression status of spermidine/spermine N-1-acetyltransferase alters body fat accumulation by metabolically modulating tissue acetyl- and malonyl-CoA levels, thereby influencing fatty acid biosynthesis and oxidation.