{"doi":"10.1016/j.jcmgh.2021.05.010","title":"Nonalcoholic Steatohepatitis and HCC in a Hyperphagic Mouse Accelerated by Western Diet","abstract":"BACKGROUND & AIMS: How benign liver steatosis progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) remains elusive. NASH progression entails diverse pathogenic mechanisms and relies on complex cross-talk between multiple tissues such as the gut, adipose tissues, liver, and the brain. Using a hyperphagic mouse fed with a Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extrahepatic alterations during NASH-HCC progression, as well as regression. METHODS: Hyperphagic mice lacking a functional Alms1 gene (Foz/Foz) and wild-type littermates were fed WD or standard chow for 12 weeks for NASH/fibrosis and for 24 weeks for HCC development. NASH regression was modeled by switching back to normal chow after NASH development. RESULTS: Foz+WD mice were steatotic within 1 to 2 weeks, developed NASH by 4 weeks, and grade 3 fibrosis by 12 weeks, accompanied by chronic kidney injury. Foz+WD mice that continued on WD progressed to cirrhosis and HCC within 24 weeks and had reduced survival as a result of cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival, and did not develop HCC. Transcriptomic and histologic analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation. This led to acute-phase liver inflammation in Foz+WD mice, characterized by neutrophil infiltration and increased levels of several chemokines/cytokines. The liver cytokine/chemokine profile evolved as NASH progressed, with subsequent predominance by monocyte recruitment. CONCLUSIONS: The Foz+WD model closely mimics the pathobiology and gene signature of human NASH with fibrosis and subsequent HCC. Foz+WD mice provide a robust and relevant preclinical model of NASH, NASH-associated HCC, chronic kidney injury, and heart failure.","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2021,"id":157206,"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":51,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"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":664219,"name":"German Aleman Muench","orcid":null,"position":1,"is_corresponding":false},{"id":248559,"name":"Linshan Shang","orcid":null,"position":2,"is_corresponding":false},{"id":103666,"name":"Sara Brin Rosenthal","orcid":"0000-0002-9072-8032","position":3,"is_corresponding":false},{"id":555809,"name":"Gibraan Rahman","orcid":"0000-0002-8843-0229","position":4,"is_corresponding":false},{"id":636481,"name":"Ruoyu Wang","orcid":"0000-0002-3644-1284","position":5,"is_corresponding":false},{"id":331811,"name":"Yanhan Wang","orcid":"0000-0001-6935-0971","position":6,"is_corresponding":false},{"id":663545,"name":"Hyeok Choon Kwon","orcid":"0000-0003-3740-3033","position":7,"is_corresponding":false},{"id":664220,"name":"Anthony Diomino","orcid":null,"position":8,"is_corresponding":false},{"id":226038,"name":"Tatiana Kisseleva","orcid":"0000-0001-9107-2306","position":9,"is_corresponding":false},{"id":664221,"name":"Pejman Soorosh","orcid":null,"position":10,"is_corresponding":false},{"id":228442,"name":"Mojgan Hosseini","orcid":"0000-0002-6708-7126","position":11,"is_corresponding":false},{"id":3554,"name":"Rob Knight","orcid":"0000-0002-0975-9019","position":12,"is_corresponding":false},{"id":239670,"name":"Bernd Schnabl","orcid":"0000-0002-6281-825X","position":13,"is_corresponding":false},{"id":232503,"name":"David A. Brenner","orcid":"0000-0003-2573-525X","position":14,"is_corresponding":false},{"id":374126,"name":"Debanjan Dhar","orcid":"0000-0001-8739-3684","position":15,"is_corresponding":false},{"id":664218,"name":"Souradipta Ganguly","orcid":null,"position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-18T23:44:17.471040Z","pmid":"34062281","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":[]}