These authors contributed equally to this work.
Caveolin-1 is essential for protecting against binge drinking-induced liver damage through inhibiting reactive nitrogen species
Article first published online: 19 MAY 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 60, Issue 2, pages 687–699, August 2014
How to Cite
Gao, L., Zhou, Y., Zhong, W., Zhao, X., Chen, C., Chen, X., Gu, Y., Chen, J., Lv, Z. and Shen, J. (2014), Caveolin-1 is essential for protecting against binge drinking-induced liver damage through inhibiting reactive nitrogen species. Hepatology, 60: 687–699. doi: 10.1002/hep.27162
Potential conflict of interest: Nothing to report.
This work was supported by the Seed Funding Program for Basic Research (no. 201111159021), the Seed Funding Program for Applied Research (no. 201109160022), The University of Hong Kong, and the General Research Fund, Hong Kong SAR (HKU 777611M).
- Issue published online: 22 JUL 2014
- Article first published online: 19 MAY 2014
- Accepted manuscript online: 8 APR 2014 03:12AM EST
- Manuscript Accepted: 2 APR 2014
- Manuscript Received: 29 NOV 2013
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. (Hepatology 2014;60:687–699)