{"doi":"10.3390/cells11091591","title":"RETRACTED: The Effects of Taurocholic Acid on Biliary Damage and Liver Fibrosis Are Mediated by Calcitonin-Gene-Related Peptide Signaling","abstract":"Background & aims: Cholangiocytes are the target cells of liver diseases that are characterized by biliary senescence (evidenced by enhanced levels of senescence-associated secretory phenotype, SASP, e.g., TGF-β1), and liver inflammation and fibrosis accompanied by altered bile acid (BA) homeostasis. Taurocholic acid (TC) stimulates biliary hyperplasia by activation of 3′,5′-cyclic cyclic adenosine monophosphate (cAMP) signaling, thereby preventing biliary damage (caused by cholinergic/adrenergic denervation) through enhanced liver angiogenesis. Also: (i) α-calcitonin gene-related peptide (α-CGRP, which activates the calcitonin receptor-like receptor, CRLR), stimulates biliary proliferation/senescence and liver fibrosis by enhanced biliary secretion of SASPs; and (ii) knock-out of α-CGRP reduces these phenotypes by decreased cAMP levels in cholestatic models. We aimed to demonstrate that TC effects on liver phenotypes are dependent on changes in the α-CGRP/CALCRL/cAMP/PKA/ERK1/2/TGF-β1/VEGF axis. Methods: Wild-type and α-CGRP−/− mice were fed with a control (BAC) or TC diet for 1 or 2 wk. We measured: (i) CGRP levels by both ELISA kits in serum and by qPCR in isolated cholangiocytes (CALCA gene for α-CGRP); (ii) CALCRL immunoreactivity by immunohistochemistry (IHC) in liver sections; (iii) liver histology, intrahepatic biliary mass, biliary senescence (by β-GAL staining and double immunofluorescence (IF) for p16/CK19), and liver fibrosis (by Red Sirius staining and double IF for collagen/CK19 in liver sections), as well as by qPCR for senescence markers in isolated cholangiocytes; and (iv) phosphorylation of PKA/ERK1/2, immunoreactivity of TGF-β1/TGF- βRI and angiogenic factors by IHC/immunofluorescence in liver sections and qPCR in isolated cholangiocytes. We measured changes in BA composition in total liver by liquid chromatography/mass spectrometry. Results: TC feeding increased CALCA expression, biliary damage, and liver inflammation and fibrosis, as well as phenotypes that were associated with enhanced immunoreactivity of the PKA/ERK1/2/TGF-β1/TGF-βRI/VEGF axis compared to BAC-fed mice and phenotypes that were reversed in α-CGRP−/− mice fed TC coupled with changes in hepatic BA composition. Conclusion: Modulation of the TC/ α-CGRP/CALCRL/PKA/ERK1/2/TGF-β1/VEGF axis may be important in the management of cholangiopathies characterized by BA accumulation.","journal":"Cells","year":2022,"id":259812,"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":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9617,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":257777,"name":"Ludovica Ceci","orcid":"0000-0002-2131-8494","position":1,"is_corresponding":false},{"id":257783,"name":"Lindsey Kennedy","orcid":"0000-0001-9224-8940","position":2,"is_corresponding":false},{"id":257785,"name":"Heather Francis","orcid":"0000-0002-3466-3545","position":3,"is_corresponding":false},{"id":314387,"name":"Vik Meadows","orcid":"0000-0002-8983-4305","position":4,"is_corresponding":false},{"id":257778,"name":"Lixian Chen","orcid":"0000-0001-9413-4592","position":5,"is_corresponding":false},{"id":70025,"name":"Guido Carpino","orcid":"0000-0001-8570-2519","position":6,"is_corresponding":false},{"id":257780,"name":"Konstantina Kyritsi","orcid":"0000-0002-7424-2788","position":7,"is_corresponding":false},{"id":257773,"name":"Nan Wu","orcid":"0000-0003-0100-6474","position":8,"is_corresponding":false},{"id":257781,"name":"Tianhao Zhou","orcid":"0000-0002-5722-6954","position":9,"is_corresponding":false},{"id":257775,"name":"Keisaku Sato","orcid":"0000-0001-5380-8001","position":10,"is_corresponding":false},{"id":912462,"name":"Luigi Pannarale","orcid":"0000-0002-3505-5066","position":11,"is_corresponding":false},{"id":257784,"name":"Shannon Glaser","orcid":"0000-0002-0749-773X","position":12,"is_corresponding":false},{"id":329676,"name":"Sanjukta Chakraborty","orcid":"0000-0002-4869-3198","position":13,"is_corresponding":false},{"id":257786,"name":"Gianfranco Alpini","orcid":"0000-0002-6658-3021","position":14,"is_corresponding":false},{"id":279143,"name":"Eugenio Gaudio","orcid":"0000-0001-6180-3091","position":15,"is_corresponding":false},{"id":279142,"name":"Paolo Onori","orcid":"0000-0002-7195-3760","position":16,"is_corresponding":false},{"id":279141,"name":"Antonio Franchitto","orcid":"0000-0003-0822-3690","position":17,"is_corresponding":false},{"id":434537,"name":"Romina Mancinelli","orcid":"0000-0003-2040-0581","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T00:25:58.993402Z","pmid":"35563897","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":[]}