Choi Joseph, Smith Danielle M, Scafidi Susanna, Riddle Ryan C, Wolfgang Michael J
Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Cell Rep. 2024 Dec 24;43(12):115006. doi: 10.1016/j.celrep.2024.115006. Epub 2024 Dec 12.
Mitochondrial fatty acid oxidation is facilitated by the combined activities of carnitine palmitoyltransferase 1 (Cpt1) and Cpt2, which generate and utilize acylcarnitines, respectively. We compare the response of mice with liver-specific deficiencies in the liver-enriched Cpt1a or the ubiquitously expressed Cpt2 and discover that they display unique metabolic, physiological, and molecular phenotypes. The loss of Cpt1a or Cpt2 results in the induction of the muscle-enriched isoenzyme Cpt1b in hepatocytes in a Pparα-dependent manner. However, hepatic Cpt1b does not contribute substantively to hepatic fatty acid oxidation when Cpt1a is absent. Liver-specific double knockout of Cpt1a and Cpt1b or Cpt2 eliminates the mitochondrial oxidation of non-esterified fatty acids. However, Cpt1a/Cpt1b double knockout mice retain fatty acid oxidation by utilizing extracellular long-chain acylcarnitines that are dependent on Cpt2. These data demonstrate the non-cell-autonomous intercellular metabolism of fatty acids in hepatocytes.
肉碱棕榈酰转移酶1（Cpt1）和Cpt2的联合活性促进了线粒体脂肪酸氧化，它们分别生成和利用酰基肉碱。我们比较了肝脏中富含肝脏特异性Cpt1a或普遍表达的Cpt2的基因缺陷小鼠的反应，发现它们表现出独特的代谢、生理和分子表型。Cpt1a或Cpt2的缺失导致以过氧化物酶体增殖物激活受体α（Pparα）依赖的方式在肝细胞中诱导肌肉中富含的同工酶Cpt1b。然而，当Cpt1a缺失时，肝脏中的Cpt1b对肝脏脂肪酸氧化没有实质性贡献。肝脏特异性敲除Cpt1a和Cpt1b或Cpt2可消除非酯化脂肪酸的线粒体氧化。然而，Cpt1a/Cpt1b双敲除小鼠通过利用依赖于Cpt2的细胞外长链酰基肉碱来保留脂肪酸氧化。这些数据证明了肝细胞中脂肪酸的非细胞自主细胞间代谢。
