Caveolin-1 is essential for protecting against binge drinking-induced liver damage through inhibiting reactive nitrogen species.
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.
School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
Lei
L
Gao
Yingchun
Y
Zhou
Weichao
W
Zhong
Xiaohua
X
Zhao
Chun
C
Chen
Xingmiao
X
Chen
Yong
Y
Gu
Jianping
J
Chen
Zhiping
Z
Lv
Jiangang
J
Shen
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D063425:Binge Drinking / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009566:Nitrates / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055815:Young Adult
C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D002492:Central Nervous System Depressants; D009566:Nitrates; D009573:Nitrites; D026361:Reactive Nitrogen Species; D030421:Peroxynitrous Acid; D000431:Ethanol; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse