{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:57:34Z","timestamp":1790092654113,"version":"4.0.1"},"reference-count":33,"publisher":"American Society for Clinical Investigation","issue":"15","license":[{"start":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T00:00:00Z","timestamp":1659916800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81922012,81770583,32171123"],"award-info":[{"award-number":["81922012,81770583,32171123"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Outstanding Youth Science Foundation of Chongqing","award":["cstc2021jcyj-jqX0005"],"award-info":[{"award-number":["cstc2021jcyj-jqX0005"]}]},{"name":"Project of Chongqing Universities Innovation Research Group","award":["2021cqspt01"],"award-info":[{"award-number":["2021cqspt01"]}]},{"name":"Natural Science Foundation of Southwest Hospital","award":["2017YQRC-01"],"award-info":[{"award-number":["2017YQRC-01"]}]},{"name":"Natural Science Foundation of Southwest Hospital","award":["XZ-2019-505-001"],"award-info":[{"award-number":["XZ-2019-505-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,8]]},"abstract":"\n Genetic polymorphisms are associated with the development of nonalcoholic fatty liver disease (NAFLD).\n Semaphorin7a<\/jats:italic>\n (\n Sema7a<\/jats:italic>\n ) deficiency in mouse peritoneal macrophages reduces fatty acid (FA) oxidation. Here, we identified 17 individuals with\n SEMA7A<\/jats:italic>\n heterozygous mutations in 470 patients with biopsy-proven NAFLD.\n SEMA7A<\/jats:italic>\n heterozygous mutations increased susceptibility to NAFLD, steatosis severity, and NAFLD activity scores in humans and mice. The\n Sema7a<\/jats:italic>\n R145W<\/jats:sup>\n mutation (equivalent to human\n SEMA7A<\/jats:italic>\n R148W<\/jats:sup>\n ) significantly induced small lipid droplet accumulation in mouse livers compared with WT mouse livers. Mechanistically, the\n Sema7a<\/jats:italic>\n R145W<\/jats:sup>\n mutation increased N-glycosylated Sema7a and its receptor integrin \u03b21 proteins in the cell membranes of hepatocytes. Furthermore,\n Sema7a<\/jats:italic>\n R145W<\/jats:sup>\n mutation enhanced its protein interaction with integrin \u03b21 and PKC-\u03b1 and increased PKC-\u03b1 phosphorylation, which were both abrogated by integrin \u03b21 silencing. Induction of\n PKC<\/jats:italic>\n \u03b1<\/jats:italic>\n _WT, but not\n PKC<\/jats:italic>\n \u03b1<\/jats:italic>\n _dominant negative, overexpression induced transcriptional factors Srebp1, Chrebp, and Lxr expression and their downstream Acc1, Fasn, and Cd36 expression in primary mouse hepatocytes. Collectively, our findings demonstrate that the\n SEMA7A<\/jats:italic>\n R148W<\/jats:sup>\n mutation is a potentially new strong genetic determinant of NAFLD and promotes intrahepatic lipid accumulation and NAFLD in mice by enhancing PKC-\u03b1\u2013stimulated FA and triglyceride synthesis and FA uptake. The inhibition of hepatic PKC-\u03b1 signaling may lead to novel NAFLD therapies.\n <\/jats:p>","DOI":"10.1172\/jci.insight.154113","type":"journal-article","created":{"date-parts":[[2022,8,7]],"date-time":"2022-08-07T14:00:41Z","timestamp":1659880841000},"source":"Crossref","is-referenced-by-count":19,"title":["SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface"],"prefix":"10.1172","volume":"7","author":[{"given":"Nan","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1033-3098","authenticated-orcid":true,"given":"Qiong","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4984-2631","authenticated-orcid":true,"given":"Ming-Hua","family":"Zheng","sequence":"additional","affiliation":[{"name":"NAFLD Research Center, Department of Hepatology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Yue","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0204-5646","authenticated-orcid":true,"given":"Jiaquan","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingqiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9027-7307","authenticated-orcid":true,"given":"Ling","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoling","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinglin","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1109-5709","authenticated-orcid":true,"given":"Lingyun","family":"Zou","sequence":"additional","affiliation":[{"name":"Bioinformatics Center, Department of Microbiology of Third Military Medical University, Chongqing, China."},{"name":"Bao\u2019an Maternal and Child Health Hospital of Jinan University, Shenzhen, 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