Abstract
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.
Highlights
Cholestatic liver diseases are characterized by cholestasis, bile duct injury, and fibrosis [1]
Oxidative stress is considered to be a key contributor to cholestatic liver diseases [3,4]
We demonstrated that the pharmacological induction of Heme oxygenase-1 (HO-1) by cobalt protoporphyrin (CoPP) ameliorated cholestatic liver injury and fibrosis by suppressing oxidative stress, hepatocyte apoptosis, and inflammation
Summary
Cholestatic liver diseases are characterized by cholestasis, bile duct injury, and fibrosis [1]. Despite largely expanded research efforts in recent decades, cholestatic liver diseases still remain as the main contributors to liver-associated morbidity and mortality [2]. Liver transplantation is the mainstay therapy for these diseases, and there are no effective medical therapies. The pathogenesis of cholestatic liver diseases remains incompletely understood, oxidative stress is considered to be one of the important pathogenic factors [3,4]. Previous human studies have reported that oxidative stress was increased in patients suffering from cholestatic liver diseases [5,6]. Animals with cholestatic liver injury exhibited increased expression of oxidative stress markers in the liver [7,8]
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