Abstract
BackgroundCholestasis is a pathological condition involving obstruction of bile secretion and excretion that results in hepatotoxicity, inflammation, fibrosis, cirrhosis, and eventually liver failure. Common bile duct ligation (BDL) model is a well-established murine model to mimic cholestatic liver fibrosis. We previously reported that cytochrome P450 omega-hydroxylase 4a14 (Cyp4a14) plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD)-related fibrosis. The goal of this study was to determine the role of Cyp4a14 in cholestatic-induced liver fibrosis.MethodsC57BL/6 mice were subjected to BDL for 14 days, and Cyp4a14 mRNA and protein levels were examined and compared with those of the sham group. Cyp4a14 knockout mice and adeno-associated virus (AAV)-mediated overexpression of Cyp4a14 in C57BL/6 mice underwent BDL and liver histology, and key fibrosis markers were examined.ResultsBoth hepatic Cyp4a14 mRNA and protein levels were markedly reduced in BDL liver compared with the time-matched sham group. Cyp4a14 gene-deficient mice aggravates whereas its overexpression alleviates BDL-induced hepatic fibrosis, which were determined by liver function, liver histology, and levels of key fibrotic markers including α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and collagen 1a2 (Col1a2).ConclusionCyp4a14 exerts a contrasting role in different hepatic fibrosis models. Strategies that enhance Cyp4a14 activity may be potential strategies to cholestatic related liver fibrosis.
Highlights
Liver fibrosis is a progressive pathological process of most chronic liver diseases with a global prevalence of more than 2%
cytochrome P450 omega-hydroxylase 4a14 (Cyp4a14) protein expression was reduced to 15% in the sham-operated mice (Figure 1B)
The decrease of Cyp4a14 in bile duct ligation (BDL) model is opposite with non-alcoholic fatty liver disease (NAFLD) murine model such as high fat diet (HFD)treated mice, db/db mice, and methionine and choline-deficient (MCD) diet-treated mice (Zhang et al, 2017)
Summary
Liver fibrosis is a progressive pathological process of most chronic liver diseases with a global prevalence of more than 2%. It is characterized by excess accumulation of extracellular matrix (ECM; Aydin and Akcali, 2018). Because of the complicated mechanisms in the progression of liver fibrosis (Parola and Pinzani, 2019; Seki and Brenner, 2015), even though we have made considerable progress in the prevention and treatment of liver fibrosis, treatment of liver fibrosis remains limited (Altamirano-Barrera et al, 2017; Roehlen et al, 2020). The underlying mechanism remains obscure, the mechanistic basis of which the fibrotic response is an area of current investigation. The goal of this study was to determine the role of Cyp4a14 in cholestatic-induced liver fibrosis
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