Hepatic Fatty Acid Oxidation Restrains Systemic Catabolism during Starvation

Cell Rep. 2016 Jun 28;16(1):201-212. doi: 10.1016/j.celrep.2016.05.062. Epub 2016 Jun 16.

Abstract

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 (Cpt2(L-/-)), 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 Cpt2(L-/-) 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 Cpt2(L-/-) 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.

MeSH terms

  • 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

Substances

  • Blood Glucose
  • Fatty Acids
  • PPAR alpha
  • Triglycerides
  • acylcarnitine
  • Carnitine O-Palmitoyltransferase
  • Carnitine