Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid

Abstract

Background and Aims Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for liver diseases. Yet, differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70 -ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential (patho)physiological consequences of their absence are unknown. We therefore assessed age- and gender-dependent effects of Cyp2c70 -deficiency in mice. Methods The consequences of Cyp2c70 -deficiency were assessed in male and female mice at different ages. Results Cyp2c70 -/- mice were devoid of MCAs and showed high abundances of chenodeoxycholic and lithocholic acids. Cyp2c70 -deficiency profoundly impacted microbiome composition. Bile flow and biliary BA secretion were normal in Cyp2c70 -/- mice of both sexes. Yet, the pathophysiological consequences of Cyp2c70 -deficiency differed considerably between sexes. Three-week old male Cyp2c70 -/- mice showed high plasma BAs and transaminases, which spontaneously decreased thereafter to near-normal levels. Only mild ductular reactions were observed in male Cyp2c70 -/- mice up to 8 months of age. In female Cyp2c70 -/- mice, plasma BAs and transaminases remained substantially elevated with age, gut barrier function was impaired and bridging fibrosis was observed at advanced age. Addition of 0.1% ursodeoxycholic acid to the diet fully normalized hepatic and intestinal functions in female Cyp2c70 -/- mice. Conclusion Cyp2c70 -/- mice show transient neonatal cholestasis and develop cholangiopathic features that progress to bridging fibrosis in females only. These consequences of Cyp2c70 -deficiency are restored by treatment with UDCA, indicating a role of BA hydrophobicity in disease development.

Absence of muricholic acid due to Cyp2c-deficiency protects against high fat diet-induced obesity in male mice but promotes liver damage

“…On the other hand, non-12α-OH BAs were significantly increased, leading to a significant decrease in the ratio of 12α-OH/non-12α-OH BAs (Figure 1G and Table 1). This is consistent with what was observed in Cyp2c70-deficient mice [20,30]. MCA is considered a hydrophilic BA, therefore its depletion and resultant alteration in BA composition increased the hydrophobicity index of BA pool in the Cyp2c −/− mice as calculated according to Heuman [31] (Figure 1H).…”

“…Furthermore, we show that contrary to predictions, MCA depletion results in impaired lipid absorption and protection against high fat diet-induced obesity in male mice. Additionally, Cyp2c deficiency promotes mild and severe liver injury in male and female mice, respectively, consistent with a recent publication [30].…”

“…Finally, our study shows liver damage in the Cyp2c −/− mice, which appears more severe in females than males as also recently reported [30]. It has previously been observed that elevated levels of certain BAs including LCA and CDCA can be hepatotoxic [37,38].…”

“…In our study as well as the studies in Cyp2c70-knockdown mice, observed downregulation of the LDLreceptor potentially contributes to the elevated LDL-cholesterol [30,32]. Another change we observed was the improvement in glucose metabolism.…”

“…The copyright holder for this preprint (which this version posted May 10, 2021. ; https://doi.org/10.1101/2021.05.10.443487 doi: bioRxiv preprint 20 contribute to the liver damage phenotypes in the Cyp2c -/mice as others have suggested [30]. Because Cyp2c enzymes are also involved in drug metabolism and detoxifying xenobiotics [41,42], we cannot rule out that these roles also contribute to the effects of Cyp2c deletion on liver damage.…”