Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury

Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice

“…A recent study reported that OCA single treatment for 4 weeks failed to alleviate cholangiopathy or portal fibrosis when the OCA treatment was initiated in 12 weeks old female Cyp2c70 KO mice ( 43 ). Another recent study reported that treating 4 weeks old female Cyp2c70 KO mice with an ASBT inhibitor SC-435 for 8 weeks fully prevented cholangiopathy and fibrosis ( 17 ). These findings collectively suggest that liver cholangiopathy and portal fibrosis become more difficult to reverse with interventions as they progress rapidly with age in the female Cyp2c70 KO mice.…”

“…Because patients with various forms of genetic and acquired cholestasis may presumably benefit from a higher degree of bile acid pool reduction that may not be achieved by a monotherapy, we further investigated the therapeutic benefits of combining GSK and AAV-FGF15 in alleviating hepatobiliary bile acid toxicity in the Cyp2c70 KO mice that were generated recently in our lab. CYP2C70 mediates the synthesis of muricholic acids (MCAs) primarily from chenodeoxycholic acid (CDCA) in mice and is responsible for the species difference of primary bile acids in humans and mice ( 14 , 15 , 16 , 17 ). In comparison to human bile acid pool, the significantly less hydrophobic bile acid pool due to the presence of MCAs in mice has been a limitation of investigating bile acid-induced hepatobiliary toxicity and the pathological impact of altered bile acid composition observed in WT mice cannot be extrapolated to humans ( 18 ).…”

Bile acids as metabolic regulators: an update

“…Although Cyp2c70 KO mice have been considered to have a ‘human-like’ bile acid pool composition, there are still several notable differences that distinguish the bile acid composition of Cyp2c70 KO mice to that of humans. Several studies have shown that the bile acid pool in Cyp2c70 KO mice contains 60–70% of CDCA and only 15–30% of CA, and only trace amount of DCA [8 ▪ ,9,10 ▪ ]. This might be a result of markedly repressed hepatic CYP8B1 expression in Cyp2c70 KO mice while altered gut bacterial-mediated DCA synthesis cannot be ruled out.…”

“…Knockout of Cyp2a12 on the Cyp2c70 KO background resulted in a bile acid pool with increased DCA and LCA [9]. The Cyp2c70 KO mice show spontaneous cholangiopathy characterized by portal inflammation, ductular reaction, and portal fibrosis [8 ▪ ,9,10 ▪ ]. In addition, female Cyp2c70 KO mice show more severe cholangiopathy that progress with age, while the liver pathology is more self-limiting in male Cyp2c70 KO mice [10 ▪ ].…”

“…Reduction in either bile acid exposure or bile acid pool hydrophobicity index alleviates liver injury in the Cyp2c70 KO mice. Perhaps not very surprising, treatments that cause a shift in CA to MCA abundance to alter bile acid pool hydrophobicity fail to do so in the Cyp2c70 KO mice [8 ▪ ,14]. Mice are a valuable experimental model for bile acid research.…”