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Growing evidence suggests that NAFLD alters the production of hepatokines, which, in turn, influence several metabolic processes. Despite accumulating evidence on the major role of estrogen signaling in the sexually dimorphic nature of NAFLD, dependency of hepatokine expression on sex and estrogens has been poorly investigated. Through in vitro and in vivo analysis, we determined the extent to which hepatokines, known to be altered in NAFLD, can be regulated, in a sex-specific fashion, under different hormonal and nutritional conditions. Our study identified four hepatokines that better recapitulate sex and estrogen dependency. Among them, adropin resulted as one that displays a sex-specific and estrogen receptor alpha (ER\u03b1)-dependent regulation in the liver of mice under an excess of dietary lipids (high-fat diet, HFD). Under HFD conditions, the hepatic induction of adropin negatively correlates with the expression of lipogenic genes and with fatty liver in female mice, an effect that depends upon hepatic ER\u03b1. Our findings support the idea that ER\u03b1-mediated induction of adropin might represent a potential approach to limit or prevent NAFLD.<\/jats:p>","DOI":"10.3390\/nu14163262","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T09:42:56Z","timestamp":1660124576000},"page":"3262","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["ER\u03b1-Dependent Regulation of Adropin Predicts Sex Differences in Liver Homeostasis during High-Fat Diet"],"prefix":"10.3390","volume":"14","author":[{"given":"Clara","family":"Meda","sequence":"first","affiliation":[{"name":"Department of Health Sciences, University of Milan, 20146 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Dolce","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Vegeto","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Maggi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9498-5266","authenticated-orcid":false,"given":"Sara","family":"Della Torre","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","article-title":"Mechanisms and Disease Consequences of Nonalcoholic Fatty Liver Disease","volume":"184","author":"Loomba","year":"2021","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1016\/S0140-6736(20)32511-3","article-title":"Non-Alcoholic Fatty Liver Disease","volume":"397","author":"Powell","year":"2021","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1002\/hep.31807","article-title":"Ten Thousand Points of Light: Heterogeneity Among the Stars of NASH Fibrosis","volume":"74","author":"Carter","year":"2021","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41575-021-00523-4","article-title":"Advancing the Global Public Health Agenda for NAFLD: A Consensus Statement","volume":"19","author":"Lazarus","year":"2022","journal-title":"Nat. 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