Heme Oxygenase-1 Induction by Cobalt Protoporphyrin Ameliorates Cholestatic Liver Disease in a Xenobiotic-Induced Murine Model

• Published in: International journal of molecular sciences 2021-08, Vol.22 (15), p.8253
• Main Authors: Kim, Jung-Yeon, Choi, Yongmin, Leem, Jaechan, Song, Jeong Eun
• Format: Article
• Language: English
• Subjects: Animal models; Antioxidants; Apoptosis; Chemokines; Cholestasis; cholestatic liver disease; Cobalt; Cytokines; Enzymes; Extracellular matrix; Fibrosis; Gallbladder diseases; Gene expression; Growth factors; Heme; Heme oxygenase (decyclizing); heme oxygenase-1; Inflammation; Inflammatory diseases; Ligands; Lipid peroxidation; Liver; Liver diseases; Oxidative stress; Oxygenase; Pathogenesis; Pharmacology; Proteins; Protoporphyrin; Quality of life; Transforming growth factor-b; Tumor necrosis factor-TNF
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22158253

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.