{"doi":"10.1016/j.jcmgh.2021.01.005","title":"Gender and Age Differences in the Hepatic Consequences of “Humanized” Bile Acid Compositions in Mice","abstract":"Bile acids (BA) are increasingly being appreciated beyond their lipid solubilizing properties as complex signaling molecules that are intricately involved in the regulation of metabolic homeostasis. Accumulation of BAs is also known to be a driving force behind cholestatic liver injuries.1Fickert P. Wagner M. Biliary bile acids in hepatobiliary injury-What is the link?.J Hepatol. 2017; 67: 619-631Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar,2Chiang J. Bile acid metabolism and signaling in liver disease and therapy.Liver Res. 2017; 1: 3-9Crossref PubMed Scopus (114) Google Scholar Although mouse models have long been used to study important aspects of BA metabolism, there are substantial differences between humans and mice in terms of BA pool composition and signaling potential, highlighting the difficulties in directly extrapolating mice findings to BA-related liver diseases in humans.3Li J. Dawson P.A. Animal models to study bile acid metabolism.Bioch Biophys Acta Mol Basis Dis. 2019; 1865: 895-911Crossref PubMed Scopus (67) Google Scholar For example, compared with humans, rodents possess a significantly more hydrophilic BA pool because of the abundant presence of muricholic acids, a set of primary BAs hydroxylated at the 6-β position, making them much more water-soluble and less injurious. This, along with other species differences in BA composition, may explain why murine models of cholestasis fail to recapitulate the totality or severity of human diseases, and points to the urgent need to develop mouse models with “humanized” BA pool. A recent landmark study published in the Journal of Lipid Research using Cyp2c-cluster null (Cyp2c null) mice followed by cellular recombinant analyses identified CYP2C70 as the enzyme necessary for the formation muricholic acids.4Takahashi S. Fukami T. Masuo Y. et al.Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans.J Lipid Res. 2016; 57: 2130-2137Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar These Cyp2c null mice possessed a more human-like and hydrophobic BA profile. Two subsequent studies using CRISPR/Cas9-generated Cyp2c70 knockout mice further confirmed the importance of this enzyme in the synthesis of 6-hydroxylated BAs and provided some surprising insights into how “a more humanized” BA composition impacts BA homeostasis and signaling. For example, increased levels of chenodeoxycholic acid observed in Cyp2c70-deficient mice as a result of blocking its conversion to muricholic acid did not lead to stronger farnesoid X receptor activation as expected because chenodeoxycholic acid is the most potent endogenous farnesoid X receptor activator5Makishima M. Okamoto A.Y. Repa J.J. et al.Identification of a nuclear receptor for bile acids.Science. 1999; 284: 1362-1365Crossref PubMed Scopus (2065) Google Scholar; instead, the cytokine and c-Jun N-terminal kinase signaling pathway was activated, potentially leading to the transaminitis and hepatic inflammation observed in these animals.6de Boer J.F. Verkade E. Mulder N.L. et al.A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of farnesoid X receptor activation in mice.J Lipid Res. 2020; 61: 291-305Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar,7Honda A. Miyazaki T. Iwamoto J. et al.Regulation of bile acid metabolism in mouse models with hydrophobic bile acid composition.J Lipid Res. 2020; 61: 54-69Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar In the current issue of Cellular and Molecular Gastroenterology and Hepatology, de Boer et al8de Boer J.F. de Vries H.D. Palmiotti A. et al.Cholangiopathy and biliary fibrosis in Cyp2c70-deficient mice are fully reversed by ursodeoxycholic acid.Cell Mol Gastroenterol Hepatol. 2021; 11: 1045-1069Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar further interrogated the pathophysiological consequences of global Cyp2c70 deleti","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2021,"id":223139,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":580801,"name":"Xiao Ming Zhao","orcid":null,"position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-18T23:54:07.287704Z","pmid":"33561440","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}