SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface
Genetic polymorphisms are associated with the development of nonalcoholic fatty liver disease (NAFLD). Semaphorin7a (Sema7a) deficiency in mouse peritoneal macrophages reduces fatty acid (FA) oxidation. Here, we identified 17 individuals with SEMA7A heterozygous mutations in 470 patients with biopsy...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-08-01
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| Series: | JCI Insight |
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| Online Access: | https://doi.org/10.1172/jci.insight.154113 |
| _version_ | 1827768136065089536 |
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| author | Nan Zhao Xiaoxun Zhang Jingjing Ding Qiong Pan Ming-Hua Zheng Wen-Yue Liu Gang Luo Jiaquan Qu Mingqiao Li Ling Li Ying Cheng Ying Peng Qiaoling Xie Qinglin Wei Qiao Li Lingyun Zou Xinshou Ouyang Shi-Ying Cai James L. Boyer Jin Chai |
| author_facet | Nan Zhao Xiaoxun Zhang Jingjing Ding Qiong Pan Ming-Hua Zheng Wen-Yue Liu Gang Luo Jiaquan Qu Mingqiao Li Ling Li Ying Cheng Ying Peng Qiaoling Xie Qinglin Wei Qiao Li Lingyun Zou Xinshou Ouyang Shi-Ying Cai James L. Boyer Jin Chai |
| author_sort | Nan Zhao |
| collection | DOAJ |
| description | Genetic polymorphisms are associated with the development of nonalcoholic fatty liver disease (NAFLD). Semaphorin7a (Sema7a) deficiency in mouse peritoneal macrophages reduces fatty acid (FA) oxidation. Here, we identified 17 individuals with SEMA7A heterozygous mutations in 470 patients with biopsy-proven NAFLD. SEMA7A heterozygous mutations increased susceptibility to NAFLD, steatosis severity, and NAFLD activity scores in humans and mice. The Sema7aR145W mutation (equivalent to human SEMA7AR148W) significantly induced small lipid droplet accumulation in mouse livers compared with WT mouse livers. Mechanistically, the Sema7aR145W mutation increased N-glycosylated Sema7a and its receptor integrin β1 proteins in the cell membranes of hepatocytes. Furthermore, Sema7aR145W mutation enhanced its protein interaction with integrin β1 and PKC-α and increased PKC-α phosphorylation, which were both abrogated by integrin β1 silencing. Induction of PKCα_WT, but not PKCα_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 SEMA7AR148W mutation is a potentially new strong genetic determinant of NAFLD and promotes intrahepatic lipid accumulation and NAFLD in mice by enhancing PKC-α–stimulated FA and triglyceride synthesis and FA uptake. The inhibition of hepatic PKC-α signaling may lead to novel NAFLD therapies. |
| first_indexed | 2024-03-11T12:08:06Z |
| format | Article |
| id | doaj.art-bdaa9e85a20f4b9da1974b6f80d01c79 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:08:06Z |
| publishDate | 2022-08-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-bdaa9e85a20f4b9da1974b6f80d01c792023-11-07T16:24:24ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-08-01715SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surfaceNan ZhaoXiaoxun ZhangJingjing DingQiong PanMing-Hua ZhengWen-Yue LiuGang LuoJiaquan QuMingqiao LiLing LiYing ChengYing PengQiaoling XieQinglin WeiQiao LiLingyun ZouXinshou OuyangShi-Ying CaiJames L. BoyerJin ChaiGenetic polymorphisms are associated with the development of nonalcoholic fatty liver disease (NAFLD). Semaphorin7a (Sema7a) deficiency in mouse peritoneal macrophages reduces fatty acid (FA) oxidation. Here, we identified 17 individuals with SEMA7A heterozygous mutations in 470 patients with biopsy-proven NAFLD. SEMA7A heterozygous mutations increased susceptibility to NAFLD, steatosis severity, and NAFLD activity scores in humans and mice. The Sema7aR145W mutation (equivalent to human SEMA7AR148W) significantly induced small lipid droplet accumulation in mouse livers compared with WT mouse livers. Mechanistically, the Sema7aR145W mutation increased N-glycosylated Sema7a and its receptor integrin β1 proteins in the cell membranes of hepatocytes. Furthermore, Sema7aR145W mutation enhanced its protein interaction with integrin β1 and PKC-α and increased PKC-α phosphorylation, which were both abrogated by integrin β1 silencing. Induction of PKCα_WT, but not PKCα_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 SEMA7AR148W mutation is a potentially new strong genetic determinant of NAFLD and promotes intrahepatic lipid accumulation and NAFLD in mice by enhancing PKC-α–stimulated FA and triglyceride synthesis and FA uptake. The inhibition of hepatic PKC-α signaling may lead to novel NAFLD therapies.https://doi.org/10.1172/jci.insight.154113HepatologyMetabolism |
| spellingShingle | Nan Zhao Xiaoxun Zhang Jingjing Ding Qiong Pan Ming-Hua Zheng Wen-Yue Liu Gang Luo Jiaquan Qu Mingqiao Li Ling Li Ying Cheng Ying Peng Qiaoling Xie Qinglin Wei Qiao Li Lingyun Zou Xinshou Ouyang Shi-Ying Cai James L. Boyer Jin Chai SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface JCI Insight Hepatology Metabolism |
| title | SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface |
| title_full | SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface |
| title_fullStr | SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface |
| title_full_unstemmed | SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface |
| title_short | SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface |
| title_sort | sema7ar148w mutation promotes lipid accumulation and nafld progression via increased localization on the hepatocyte surface |
| topic | Hepatology Metabolism |
| url | https://doi.org/10.1172/jci.insight.154113 |
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