Caveolin-1 Is Essential for Protecting Against Binge Drinking-Induced Liver Damage Through Inhibiting Reactive Nitrogen Species

Hepatology. 2014 Aug;60(2):687-99. doi: 10.1002/hep.27162. Epub 2014 May 19.

Abstract

Caveolin-1 (Cav-1) is known to participate in many diseases, but its roles in alcoholic liver injury remain unknown. In the present study, we aimed to explore the roles of Cav-1 in protecting hepatocytes from ethanol-mediated nitrosative injury. We hypothesized that Cav-1 could attenuate ethanol-mediated nitrosative stress and liver damage through regulating epidermal growth factor receptor/signal transducer and activator of transcription 3/inducible nitric oxide synthase (EGFR/STAT3/iNOS)-signaling cascades. Ethanol-fed mice had time- and dose-dependent increases of Cav-1 in serum and liver with peak increase at 12 hours. Compared to wild-type mice, Cav-1 deficiency mice revealed higher expression of iNOS, higher levels of nitrate/nitrite and peroxynitrite, and had more serious liver damage, accompanied with higher levels of cleaved caspase-3 and apoptotic cell death in liver, and higher levels of alanine aminotransferase and aspartate aminotransferase in serum. Furthermore, the results revealed that the ethanol-mediated Cav-1 increase was in an extracellular signal-regulated kinase-dependent manner, and Cav-1 protected hepatocytes from ethanol-mediated apoptosis by inhibiting iNOS activity and regulating EGFR- and STAT3-signaling cascades. In agreement with these findings, clinical trials in human subjects revealed that serum Cav-1 level was time dependently elevated and peak concentration was observed 12 hours after binge drinking. Alcohol-induced liver lesions were negatively correlated with Cav-1 level, but positively correlated with nitrate/nitrite level, in serum of binge drinkers.

Conclusions: Cav-1 could be a cellular defense protein against alcoholic hepatic injury through inhibiting reactive nitrogen species and regulating EGFR/STAT3/iNOS-signaling cascades.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Apoptosis / physiology
  • Binge Drinking / metabolism*
  • Binge Drinking / pathology
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism*
  • Central Nervous System Depressants / administration & dosage
  • Dose-Response Relationship, Drug
  • Ethanol / administration & dosage
  • Humans
  • Liver Diseases, Alcoholic / metabolism*
  • Liver Diseases, Alcoholic / pathology
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Nitrates / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Nitrites / metabolism
  • Peroxynitrous Acid / metabolism
  • Reactive Nitrogen Species / antagonists & inhibitors
  • Reactive Nitrogen Species / metabolism*
  • Young Adult

Substances

  • CAV1 protein, human
  • Cav1 protein, mouse
  • Caveolin 1
  • Central Nervous System Depressants
  • Nitrates
  • Nitrites
  • Reactive Nitrogen Species
  • Peroxynitrous Acid
  • Ethanol
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse