Carnitine Palmitoyltransferase 1 facilitates fatty acid oxidation in a noncell autonomous manner [TKO_RNAseq]

Mitochondrial fatty acid oxidation is facilitated by the combined activities of Carnitine Palmitoyltransferase 1 and Carnitine Palmitoyltransferase 2 which generate and utilize acylcarnitines respectively. We compared the response of mice with liver specific deficiencies in Cpt1a and Cpt1b, Cpt2, or the triple deletion of all three acyltransferases. We discovered that they display unique metabolic, physiological and molecular phenotypes. The loss of Cpt1a and Cpt1b or Cpt2 resulted in particular transcriptional outputs in hepatocytes. We show that much of the transcriptional signature is suppressed when deleting both Cpt2 and Ppara, showing the contribution of Ppara. Our results utilize stringent genetic mouse models to characterize the differential phenotypes of mice lacking Cpt1a and Cpt1b or Cpt2 and also show the contribution of a major transcription factor, Ppara.线粒体脂肪酸氧化（mitochondrial fatty acid oxidation）有赖于肉碱棕榈酰转移酶1（Carnitine Palmitoyltransferase 1, CPT1）与肉碱棕榈酰转移酶2（Carnitine Palmitoyltransferase 2, CPT2）的协同催化活性，二者分别负责酰基肉碱（acylcarnitines）的生成与利用。本研究针对肝脏特异性缺失Cpt1a、Cpt1b或Cpt2，以及三重敲除全部三种酰基转移酶（acyltransferases）的小鼠模型，比较其机体响应差异。研究发现，上述各类基因修饰小鼠均呈现出独特的代谢、生理及分子表型。敲除Cpt1a与Cpt1b，或敲除Cpt2，均可使肝细胞产生特异性转录谱。本研究证实，若同时敲除Cpt2与过氧化物酶体增殖物激活受体α（Ppara），多数转录特征会受到抑制，由此揭示了Ppara的调控贡献。本研究借助严格构建的基因工程小鼠模型，系统解析了缺失Cpt1a与Cpt1b或Cpt2的小鼠的差异化表型，并阐明了核心转录因子Ppara的调控作用。