Heme Oxygenase-1 Induction by Cobalt Protoporphyrin Ameliorates Cholestatic Liver Disease in a Xenobiotic-Induced Murine Model.
Cholestatic liver diseases can progress to end-stage liver disease and reduce patients' quality of life. Although their underlying mechanisms are still incompletely elucidated, oxidative stress is considered to be a key contributor to these diseases. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that displays antioxidant action. It has been found that this enzyme plays a protective role against various inflammatory diseases. However, the role of HO-1 in cholestatic liver diseases has not yet been investigated. Here, we examined whether pharmacological induction of HO-1 by cobalt protoporphyrin (CoPP) ameliorates cholestatic liver injury. To this end, a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding was used. Administration of CoPP ameliorated liver damage and cholestasis with HO-1 upregulation in DDC diet-fed mice. Induction of HO-1 by CoPP suppressed the DDC diet-induced oxidative stress and hepatocyte apoptosis. In addition, CoPP attenuated cytokine production and inflammatory cell infiltration. Furthermore, deposition of the extracellular matrix and expression of fibrosis-related genes after DDC feeding were also decreased by CoPP. HO-1 induction decreased the number of myofibroblasts and inhibited the transforming growth factor-β pathway. Altogether, these data suggest that the pharmacological induction of HO-1 ameliorates cholestatic liver disease by suppressing oxidative stress, hepatocyte apoptosis, and inflammation.
['Kim|Jung-Yeon|JY|', 'Choi|Yongmin|Y|0000-0002-8679-5662', 'Leem|Jaechan|J|0000-0003-2329-4374', 'Song|Jeong Eun|JE|']
D000818:Animals D000893:Anti-Inflammatory Agents D000975:Antioxidants D017209:Apoptosis D002780:Cholestasis, Intrahepatic D051547:Heme Oxygenase-1 D022781:Hepatocytes D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018384:Oxidative Stress D011524:Protoporphyrins D011725:Pyridines D015262:Xenobiotics
heme oxygenase-1 cholestatic liver disease oxidative stress apoptosis inflammation fibrosis