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Local and systemic actions of hepatic fatty acid oxidation
Author(s) -
Wolfgang Michael J.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00211
Subject(s) - ketogenesis , beta oxidation , fatty acid , fatty acid metabolism , ketone bodies , starvation response , chemistry , peroxisome , gluconeogenesis , medicine , endocrinology , biochemistry , biology , metabolism , gene
Mitochondrial long chain fatty acid beta‐oxidation is required for hepatic ketogenesis and gluconeogensis during fasting, starvation and times of low carbohydrate intake. The liver has a large capacity and dynamic range for fatty acid oxidation to facilitate ketogenesis and gluconeogenesis. To gain a better understanding of the roles of hepatic fatty acid oxidation on liver function, we generated mice with a hepatocyte‐specific knockout of Carnitine Palmitoyltransferase 2 (Cpt2 L−/− ), an obligate step in mitochondrial long‐chain fatty acid β‐oxidation. Mice with a loss in hepatic fatty acid oxidation were able to maintain systemic glucose homeostasis during a 24hr fast, but did not produce ketone bodies. Systemic energy homeostasis was largely maintained by adaptations in hepatic and systemic oxidative gene expression mediated in part by a robust hepatic transcriptional response. Open chromatin assessed by ATAC‐seq and histone H3K9 ChIP‐seq analysis revealed that many genes induced in fasted Cpt2 L−/− mice exhibited Pparα regulatory sites. To understand the contribution of Pparα, we generated Pparα;Cpt2 L−/− double knockout mice. The deletion of Pparα in Cpt2 L−/− mice largely blunted this transcriptional response, demonstrating the requirement for Pparα. Triglyceride hydrolysis has been shown to be critical for Pparα‐mediated transcriptional control. To determine the requirement of hepatic triglyceride hydrolysis on the Cpt2 L−/− transcriptional response, mice were generated with a liver‐specific defect in triglyceride hydrolysis (Atgl L−/− ) and fatty acid oxidation (Atgl L−/− ;Cpt2 L−/− double knockout). The loss of Cpt2 or Atgl resulted in largely independent effects on hepatocyte morphology, intermediary metabolism and gene expression in response to fasting. However, high fat feeding revealed the interaction of Atgl and Cpt2 as the loss of only one of these genes results in steatosis but the loss of both components resulted in significant inflammation and fibrosis. These data suggest that defects in mitochondrial fatty acid oxidation induce an exaggerated fasting response that initiates lipid dependent transcription to mediate changes in local and systemic physiology. Support or Funding Information This work was supported in part by a National Institutes of Health grant R01DK116746 to M.J.W.