Dean Jason T, Tran Linh, Beaven Simon, Tontonoz Peter, Reue Karen, Dipple Katrina M, Liao James C
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA 90095, USA.
Cell Metab. 2009 Jun;9(6):525-36. doi: 10.1016/j.cmet.2009.04.008.
Given the success in engineering synthetic phenotypes in microbes and mammalian cells, constructing non-native pathways in mammals has become increasingly attractive for understanding and identifying potential targets for treating metabolic disorders. Here, we introduced the glyoxylate shunt into mouse liver to investigate mammalian fatty acid metabolism. Mice expressing the shunt showed resistance to diet-induced obesity on a high-fat diet despite similar food consumption. This was accompanied by a decrease in total fat mass, circulating leptin levels, plasma triglyceride concentration, and a signaling metabolite in liver, malonyl-CoA, that inhibits fatty acid degradation. Contrary to plants and bacteria, in which the glyoxylate shunt prevents the complete oxidation of fatty acids, this pathway when introduced in mice increases fatty acid oxidation such that resistance to diet-induced obesity develops. This work suggests that using non-native pathways in higher organisms to explore and modulate metabolism may be a useful approach.
鉴于在工程改造微生物和哺乳动物细胞的合成表型方面取得的成功，构建哺乳动物的非天然代谢途径对于理解和确定治疗代谢紊乱的潜在靶点变得越来越有吸引力。在此，我们将乙醛酸循环引入小鼠肝脏以研究哺乳动物的脂肪酸代谢。表达该循环的小鼠在高脂饮食下尽管食物摄入量相似，但对饮食诱导的肥胖具有抗性。这伴随着总脂肪量、循环瘦素水平、血浆甘油三酯浓度以及肝脏中一种抑制脂肪酸降解的信号代谢物丙二酰辅酶A的减少。与植物和细菌不同，在植物和细菌中乙醛酸循环可防止脂肪酸的完全氧化，而该途径引入小鼠后会增加脂肪酸氧化，从而产生对饮食诱导肥胖的抗性。这项工作表明，利用高等生物中的非天然代谢途径来探索和调节代谢可能是一种有用的方法。
