Caveolin-1 is essential for protecting against binge drinking-induced liver damage through inhibiting reactive nitrogen species.

Abstract

UNLABELLED:

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.

• Authors: Lei Gao, Yingchun Zhou, Weichao Zhong, Xiaohua Zhao, Chun Chen, Xingmiao Chen, Yong Gu, Jianping Chen, Zhiping Lv, Jiangang Shen
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 60 Issue 2 Pg. 687-99 (Aug 2014) ISSN: 1527-3350 [Electronic] United States
• PMID: 24710718 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by the American Association for the Study of Liver Diseases.

Chemical References

• 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

Topics

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