{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:20:46Z","timestamp":1790713246256,"version":"4.1.0"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>NAFLD, characterized by aberrant triglyceride accumulation in liver, affects the metabolic remodeling of hepatic and nonhepatic tissues by secreting altered hepatokines. Small ubiquitin\u2010related modifier (SUMO)\u2013specific protease 2 (SENP2) is responsible for de\u2010SUMOylation of target protein, with broad effects on cell growth, signal transduction, and developmental processes. However, the role of SENP2 in hepatic metabolism remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>We found that SENP2 was the most dramatically increased SENP in the fatty liver and that its level was modulated by fed\/fasted conditions. To define the role of hepatic SENP2 in metabolic regulation, we generated liver\u2010specific SENP2 knockout (Senp2\u2010LKO) mice. Senp2\u2010LKO mice exhibited resistance to high\u2010fat diet\u2013induced hepatic steatosis and obesity. RNA\u2010sequencing analysis showed that Senp2 deficiency up\u2010regulated genes involved in fatty acid oxidation and down\u2010regulated genes in lipogenesis in the liver. Additionally, ablation of hepatic SENP2 activated thermogenesis of adipose tissues. Improved energy homeostasis of both the liver and adipose tissues by SENP2 disruption prompted us to detect the hepatokines, with FGF21 identified as a key factor markedly elevated in Senp2\u2010LKO mice that maintained metabolic homeostasis. Loss of FGF21 obviously reversed the positive effects of SENP2 deficiency on metabolism. Mechanistically, by screening transcriptional factors of FGF21, peroxisome proliferator\u2013activated receptor alpha (PPAR\u03b1) was defined as the mediator for SENP2 and FGF21. SENP2 interacted with PPAR\u03b1 and deSUMOylated it, thereby promoting ubiquitylation and subsequent degradation of PPAR\u03b1, which in turn inhibited FGF21 expression and fatty acid oxidation. Consistently, SENP2 overexpression in liver facilitated development of metabolic disorders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our finding demonstrated a key role of hepatic SENP2 in governing metabolic balance by regulating liver\u2013adipose tissue crosstalk, linking the SUMOylation process to metabolic regulation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.31881","type":"journal-article","created":{"date-parts":[[2021,5,2]],"date-time":"2021-05-02T04:54:16Z","timestamp":1619931256000},"page":"1864-1883","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":61,"title":["Hepatic Small Ubiquitin\u2010Related Modifier (SUMO)\u2013Specific Protease 2 Controls Systemic Metabolism Through SUMOylation\u2010Dependent Regulation of Liver\u2013Adipose Tissue Crosstalk"],"prefix":"10.1097","volume":"74","author":[{"given":"Yang","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Dou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010yu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Ding","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruo\u2010qi","family":"Du","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Guo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu\u2010wen","family":"Qian","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi\u2010qi","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong\u2010ning","family":"Pan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010ying","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Lu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin\u2010ke","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Cell Biology,Shanghai Key Laboratory for Tumor Microenvironment and Inflammation,Shanghai Jiao Tong University School of Medicine,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi\u2010qun","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education,Department of 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