{"doi":"10.1016/j.cmet.2024.08.012","title":"IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis","abstract":"The exponential rise in metabolic dysfunction-associated steatotic liver disease (MASLD) parallels the ever-increasing consumption of energy-dense diets, underscoring the need for effective MASLD-resolving drugs. MASLD pathogenesis is linked to obesity, diabetes, \"gut-liver axis\" alterations, and defective interleukin-22 (IL-22) signaling. Although barrier-protective IL-22 blunts diet-induced metabolic alterations, inhibits lipid intake, and reverses microbial dysbiosis, obesogenic diets rapidly suppress its production by small intestine-localized innate lymphocytes. This results in STAT3 inhibition in intestinal epithelial cells (IECs) and expansion of the absorptive enterocyte compartment. These MASLD-sustaining aberrations were reversed by administration of recombinant IL-22, which resolved hepatosteatosis, inflammation, fibrosis, and insulin resistance. Exogenous IL-22 exerted its therapeutic effects through its IEC receptor, rather than hepatocytes, activating STAT3 and inhibiting WNT-β-catenin signaling to shrink the absorptive enterocyte compartment. By reversing diet-reinforced macronutrient absorption, the main source of liver lipids, IL-22 signaling restoration represents a potentially effective interception of dietary obesity and MASLD.","journal":"Cell Metabolism","year":2024,"id":418657,"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":48,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":622758,"name":"Junlai Liu","orcid":"0000-0001-6460-9569","position":1,"is_corresponding":false},{"id":316664,"name":"Allen Lee","orcid":"0000-0002-4861-7646","position":2,"is_corresponding":false},{"id":1207835,"name":"Irene Tsaur","orcid":null,"position":3,"is_corresponding":false},{"id":1207137,"name":"Masafumi Ohira","orcid":"0000-0003-0775-3390","position":4,"is_corresponding":false},{"id":992254,"name":"Vivian Duong","orcid":null,"position":5,"is_corresponding":false},{"id":1207836,"name":"Nicholas Vo","orcid":null,"position":6,"is_corresponding":false},{"id":1037223,"name":"Kosuke Watari","orcid":"0000-0003-0260-2323","position":7,"is_corresponding":false},{"id":622750,"name":"Hua Su","orcid":"0000-0003-2344-3886","position":8,"is_corresponding":false},{"id":689488,"name":"Ju Youn Kim","orcid":"0009-0003-2452-4423","position":9,"is_corresponding":false},{"id":1037222,"name":"Li Gu","orcid":"0000-0001-9508-5673","position":10,"is_corresponding":false},{"id":1207837,"name":"Mandy Zhu","orcid":null,"position":11,"is_corresponding":false},{"id":233455,"name":"Shabnam Shalapour","orcid":"0000-0002-4743-3706","position":12,"is_corresponding":false},{"id":228442,"name":"Mojgan Hosseini","orcid":"0000-0002-6708-7126","position":13,"is_corresponding":false},{"id":271692,"name":"Gautam Bandyopadhyay","orcid":"0000-0003-4347-6036","position":14,"is_corresponding":false},{"id":644613,"name":"Su-Ling Zeng","orcid":"0000-0002-2188-4285","position":15,"is_corresponding":false},{"id":647745,"name":"Cristina Llorente","orcid":"0000-0001-8135-9186","position":16,"is_corresponding":false},{"id":1207138,"name":"Haoqi Nina Zhao","orcid":"0000-0003-3908-630X","position":17,"is_corresponding":false},{"id":344334,"name":"Santosh Lamichhane","orcid":"0000-0002-9292-3595","position":18,"is_corresponding":false},{"id":1207139,"name":"Siddharth Mohan","orcid":"0009-0000-0134-0240","position":19,"is_corresponding":false},{"id":3553,"name":"Pieter C. 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