Journal
FRONTIERS IN PHYSIOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphys.2021.688259
Keywords
Cyp4a14; bile duct ligation; liver injury; liver fibrosis; cholestasis
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Funding
- National Natural Science Foundation of China [81800549, 81870405]
- Natural Science Foundation of Hebei Province, China [H2020402002]
- SZU Top Ranking Project of China [86000000210]
- SZU Medical Young Scientists Program of China [71201-000001]
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The study revealed that Cyp4a14 gene plays a role in cholestatic-induced liver fibrosis, with its deficiency exacerbating fibrosis and overexpression alleviating fibrotic symptoms. Enhancing Cyp4a14 activity may be a potential therapeutic strategy for cholestatic-related liver fibrosis.
Background Cholestasis 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. Methods C57BL/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. Results Both 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 alpha-smooth muscle actin (alpha-SMA), transforming growth factor-beta 1 (TGF-beta 1), and collagen 1a2 (Col1a2). Conclusion Cyp4a14 exerts a contrasting role in different hepatic fibrosis models. Strategies that enhance Cyp4a14 activity may be potential strategies to cholestatic related liver fibrosis.
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