Hepatic Fatty Acid Oxidation Restrains Systemic Catabolism during Starvation

• Published in: Cell reports (Cambridge) Vol. 16; no. 1; pp. 201 - 212
• Main Authors: Lee, Jieun, Choi, Joseph, Scafidi, Susanna, Wolfgang, Michael J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.06.2016; Elsevier
• Subjects: Adipose Tissue - metabolism; Animals; Blood Glucose - metabolism; Body Weight; Carnitine - analogs & derivatives; Carnitine - metabolism; Carnitine O-Palmitoyltransferase - deficiency; Carnitine O-Palmitoyltransferase - metabolism; Diet, Ketogenic; Dyslipidemias - complications; Dyslipidemias - genetics; Dyslipidemias - metabolism; Dyslipidemias - pathology; Fasting - metabolism; Fatty Acids - metabolism; Gene Expression Regulation; Lipogenesis; Liver - metabolism; Liver - pathology; Mice, Knockout; Organ Specificity; Oxidation-Reduction; Oxidative Stress; PPAR alpha - metabolism; Starvation - complications; Starvation - genetics; Starvation - metabolism; Starvation - pathology; Triglycerides - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.05.062

The liver is critical for maintaining systemic energy balance during starvation. To understand the role of hepatic fatty acid β-oxidation on this process, we generated mice with a liver-specific knockout of carnitine palmitoyltransferase 2 (Cpt2L−/−), an obligate step in mitochondrial long-chain fatty acid β-oxidation. Fasting induced hepatic steatosis and serum dyslipidemia with an absence of circulating ketones, while blood glucose remained normal. Systemic energy homeostasis was largely maintained in fasting Cpt2L−/− mice by adaptations in hepatic and systemic oxidative gene expression mediated in part by Pparα target genes including procatabolic hepatokines Fgf21, Gdf15, and Igfbp1. Feeding a ketogenic diet to Cpt2L−/− mice resulted in severe hepatomegaly, liver damage, and death with a complete absence of adipose triglyceride stores. These data show that hepatic fatty acid oxidation is not required for survival during acute food deprivation but essential for constraining adipocyte lipolysis and regulating systemic catabolism when glucose is limiting. [Display omitted] •Hepatic fatty acid oxidation (FAO) is critical for liver physiology during starvation•Hepatic FAO suppresses adipose lipolysis and systemic catabolism•Upon fasting, loss of hepatic FAO induces Pparα target genes in the liver•A ketogenic diet induces severe lipolysis and lethality in hepatic FAO-deficient mice Lee et al. have generated mice that lack mitochondrial long-chain fatty acid β-oxidation specifically in the liver. They report that these mice can survive a 24-hr fast but not a low-carbohydrate ketogenic diet. Surprisingly, whole-body energy expenditure is largely maintained due to increased peripheral catabolism.