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The corresponding nutrient signals and sensors as well as signalling pathways have not yet been well studied. This study aimed to unravel the nutrient\u2010sensing mechanisms in the pathogenesis of steatosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Plin2, a lipid droplet (LD) protein\u2010inhibiting lipolysis, is associated with steatosis in liver and muscle. Taking advantage of the Gal4\u2010UAS system, we used the <jats:styled-content style=\"fixed-case\"><jats:italic>Drosophila melanogaster<\/jats:italic><\/jats:styled-content> wing imaginal disc as an in vivo model to study the regulation of Plin2 proteostasis and LD homeostasis. <jats:italic>Drosophila<\/jats:italic> Schneider 2 (S2) cells were used for western blotting, immunoprecipitation assays, amino acid\u2010binding assays and ubiquitination assays to further investigate the regulatory mechanisms of Plin2 in response to nutrient signals. Mouse AML12 hepatocytes, human JHH\u20107 and SNU\u2010475 hepatoma cells were used for immunofluorescence, western blotting and immunoprecipitation to demonstrate that the mode of Plin2 regulation is evolutionarily conserved. In addition, we purified proteins from HEK293 cells and reconstituted in vitro cell\u2010free systems in amino acid\u2010binding assays, pulldown assays and ubiquitination assays to directly demonstrate the molecular mechanism by which Ubr1 senses amino acids to regulate Plin2 proteostasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>As a lipolysis inhibitor, Plin2 was significantly elevated in liver (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and muscle (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) in patients with steatosis. Consistently, we found that the ubiquitin moiety can be conjugated to any Lys residue in Plin2, ensuring robust clearance of Plin2 by protein degradation. We further demonstrated that the E3 ubiquitin ligase Ubr1 targets Plin2 for degradation in an amino acid\u2010dependent manner. Ubr1 uses two canonical substrate\u2010binding pockets, independent of each other, to bind basic and bulky hydrophobic amino acids, respectively. Mechanistically, amino acid binding allosterically activates Ubr1 by alleviating Ubr1's auto\u2010inhibition. In the absence of amino acids, or when the amino acid\u2010binding capacity of Ubr1 is diminished, Ubr1\u2010mediated Plin2 degradation is inactivated, leading to steatosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We identified Ubr1 as an amino acid sensor regulating Plin2 proteostasis, bridging the knowledge gap between steatosis and nutrient sensing. Our work may provide new strategies for the prevention and treatment of steatosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13233","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T07:07:12Z","timestamp":1681456032000},"page":"1454-1467","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle"],"prefix":"10.1002","volume":"14","author":[{"given":"Wanni","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery\/Clinical Nutrition, Key Laboratory of Cancer FSMP for State Market Regulation, Beijing Shijitan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yansong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Cell Proliferation and 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China"},{"name":"Peking\u2010Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanping","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery\/Clinical Nutrition, Key Laboratory of Cancer FSMP for State Market Regulation, Beijing Shijitan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8077-0130","authenticated-orcid":false,"given":"Min","family":"Liu","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences Peking University  Beijing China"},{"name":"Peking\u2010Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies Peking University  Beijing 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