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

• Published in: Hepatology (Baltimore, Md.) Vol. 60; no. 2; pp. 687 - 699
• Main Authors: Gao, Lei, Zhou, Yingchun, Zhong, Weichao, Zhao, Xiaohua, Chen, Chun, Chen, Xingmiao, Gu, Yong, Chen, Jianping, Lv, Zhiping, Shen, Jiangang
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer Health, Inc 01.08.2014
• Subjects: 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; Ethanol - administration & dosage; Hepatology; Humans; Liver; Liver Diseases, Alcoholic - metabolism; Liver Diseases, Alcoholic - pathology; Male; MAP Kinase Signaling System - physiology; 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; Rodents; Young Adult
• ISSN: 0270-9139; 1527-3350; 1527-3350
• DOI: 10.1002/hep.27162

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)