Ethanol Administration Exacerbates the Abnormalities in Hepatic Lipid Oxidation in Genetically Obese Mice

Am J Physiol Gastrointest Liver Physiol. 2013 Jan 1;304(1):G38-47. doi: 10.1152/ajpgi.00309.2012. Epub 2012 Nov 8.

Abstract

Alcohol consumption synergistically increases the risk and severity of liver damage in obese patients. To gain insight into cellular or molecular mechanisms underlying the development of fatty liver caused by ethanol-obesity synergism, we have carried out animal experiments that examine the effects of ethanol administration in genetically obese mice. Lean wild-type (WT) and obese (ob/ob) mice were subjected to ethanol feeding for 4 wk using a modified Lieber-DeCarli diet. After ethanol feeding, the ob/ob mice displayed much more pronounced changes in terms of liver steatosis and elevated plasma levels of alanine aminotransferase and aspartate aminotransferase, indicators of liver injury, compared with control mice. Mechanistic studies showed that ethanol feeding augmented the impairment of hepatic sirtuin 1 (SIRT1)-AMP-activated kinase (AMPK) signaling in the ob/ob mice. Moreover, the impairment of SIRT1-AMPK signaling was closely associated with altered hepatic functional activity of peroxisome proliferator-activated receptor γ coactivator-α and lipin-1, two vital downstream lipid regulators, which ultimately contributed to aggravated fatty liver observed in ethanol-fed ob/ob mice. Taken together, our novel findings suggest that ethanol administration to obese mice exacerbates fatty liver via impairment of the hepatic lipid metabolism pathways mediated largely by a central signaling system, the SIRT1-AMPK axis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • AMP-Activated Protein Kinases / physiology
  • Animals
  • Blotting, Western
  • Body Weight / physiology
  • Cell Nucleus / drug effects
  • Cell Nucleus / ultrastructure
  • Central Nervous System Depressants / pharmacology*
  • DNA Primers
  • Ethanol / pharmacology*
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Fluorescent Antibody Technique
  • Lipid Metabolism / drug effects*
  • Lipid Peroxidation / drug effects
  • Liver / metabolism*
  • Liver / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Nuclear Proteins / metabolism
  • Obesity / genetics*
  • Obesity / metabolism*
  • Obesity / pathology
  • Organ Size / physiology
  • Oxidation-Reduction
  • PPAR gamma / physiology
  • Phosphatidate Phosphatase / metabolism
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Sirtuin 1 / genetics
  • Sirtuin 1 / physiology

Substances

  • Central Nervous System Depressants
  • DNA Primers
  • Nuclear Proteins
  • PPAR gamma
  • Ethanol
  • AMP-Activated Protein Kinases
  • Lpin1 protein, mouse
  • Phosphatidate Phosphatase
  • Sirt1 protein, mouse
  • Sirtuin 1