Cytochrome P450 Omega-Hydroxylase 4a14 Attenuates Cholestatic Liver Fibrosis

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.

ZnT8 Deficiency Protects From APAP-Induced Acute Liver Injury by Reducing Oxidative Stress Through Upregulating Hepatic Zinc and Metallothioneins

“…We examined CYP2E1 protein expression but detected no difference between ZnT8 KO mice and control mice ( Figure 2E ). In contrast, CYP4A, another important oxidative metabolism enzyme, was markedly increased, which is consistent with our recent study showing that CYP4A has a protective effect in bile duct ligation (BDL) induced liver injury ( Figure 2E ) ( Li et al, 2021 ). We also compared the gene expression levels of other major APAP-metabolizing enzymes and transporters in the livers.…”

“…Therefore, one would suspect that enhanced PPARα activity is responsible for the increased CYP4A expression at the basal level. In addition, our recent paper showed that CYP4A exerts a protective effect in BDLinduced inflammation and liver injury, supporting the possibility that the increased CYP4A in the ZnT8 KO mice in this study may be participate in the attenuation of APAP-induced liver injury (Li et al, 2021).…”

Phosphorylation of 17β-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice

“…Total protein was prepared as described before 48 . A total of 40 μg of protein were separated by 10% SDS-PAGE and transferred to a PVDF membrane.…”

Jag1 Insufficiency Disrupts Neonatal T Cell Differentiation and Impairs Hepatocyte Maturation, Leading to Altered Liver Fibrosis

“…Azgp1 is a negative regulator of liver and pancreatic cancer progression, and inhibits TGFβ-driven epithelial to mesenchymal transition [100,101]. Cyp4a14 (cytochrome P450 omega-hydroxylase 4a14), a marker of cholestasis [102] that counteracts fibrosis [103] was upregulated in Jag1 Ndr/Ndr hepatocyte populations at P3 ( Fig. 3F, G ).…”