Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Truong, JK; Bennett, AL; Klindt, C; Donepudi, AC; Malla, SR; Pachura, KJ; Zaufel, A; Moustafa, T; Dawson, PA; Karpen, SJ.
Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury
J LIPID RES. 2022; 63(9): 100261 Doi: 10.1016/j.jlr.2022.100261 [OPEN ACCESS]
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Co-authors Med Uni Graz

Moustafa Tarek

Zaufel Alex

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Abstract:

Cyp2c70 is the liver enzyme in rodents responsible for synthesis of the primary 6hydroxylated muricholate bile acid (BA) species. Cyp2c70 KO mice are devoid of protective, hydrophilic muricholic acids, leading to a more human-like BA composition and subsequent cholestatic liver injury. Pharmacological inhibition of the ileal BA transporter (IBAT) has been shown to be therapeutic in cholestatic models. Here, we aimed to determine if IBAT inhibition with SC-435 is protective in Cyp2c70 KO mice. As compared to WT mice, we found male and female Cyp2c70 KO mice exhibited increased levels of serum liver injury markers, and our evaluation of liver histology revealed increased hepatic inflammation, macrophage infiltration, and biliary cell proliferation. We demonstrate serum and histologic markers of liver damage were markedly reduced with SC-435 treatment. Additionally, we show hepatic gene expression in pathways related to immune cell activation and inflammation were significantly upregulated in Cyp2c70 KO mice and reduced to levels indistinguishable from WT with IBAT inhibition. In Cyp2c70 KO mice, the liver BA content was significantly increased, enriched in chenodeoxycholic acid, and more hydrophobic, exhibiting a hydrophobicity index value and red blood cell lysis properties similar to human liver reduced the total hepatic BA levels but did not affect overall hydrophobicity of the liver BAs. These findings suggest that there may be a threshold in the liver for pathological accretion of hydrophobic BAs and reducing hepatic BA accumulation can be sufficient to alleviate liver injury, independent of BA pool hydrophobicity.

Find related publications in this database (Keywords)

Supplementary key words Cytochrome P450

cholesterol 7?-hydroxylase

sterol 12?-hydroxylase

hydrophobicity

detergency

enterohepatic circulation

muricholic acids

chenodeoxycholic acid

biliary cell proliferation

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