PMID- 32237906 OWN - NLM STAT- MEDLINE DCOM- 20200714 LR - 20200714 IS - 1524-4636 (Electronic) IS - 1079-5642 (Linking) VI - 40 IP - 5 DP - 2020 May TI - Integrin beta3 Deficiency Results in Hypertriglyceridemia via Disrupting LPL (Lipoprotein Lipase) Secretion. PG - 1296-1310 LID - 10.1161/ATVBAHA.119.313191 [doi] AB - OBJECTIVE: Integrin beta3 is implicated in numerous biological processes such as its relevance to blood triglyceride, yet whether beta3 deficiency affects this metabolic process remains unknown. Approach and Results: We showed that the Chinese patients with beta3-deficient Glanzmann thrombasthenia had a 2-fold higher serum triglyceride level together with a lower serum LPL (lipoprotein lipase) level than those with an alphaIIb deficiency or healthy subjects. The beta3 knockout mice recapitulated these phenotypic features. The elevated plasma triglyceride level was due to impaired LPL-mediated triglyceride clearance caused by a disrupted LPL secretion. Further analysis revealed that beta3 directly bound LPL via a juxtamembrane TIH (threonine isoleucine histidine)(720)(-722) motif in its cytoplasmic domain and functioned as an adaptor protein by interacting with LPL and PKD (protein kinase D) to form the PKD/beta3/LPL complex that is required for beta3-mediated LPL secretion. Furthermore, the impaired triglyceride clearance in beta3 knockout mice could be corrected by adeno-associated virus serotype 9 (AAV9)-mediated delivery of wild-type but not TIH(720-)(722)-mutated beta3 genes. CONCLUSIONS: This study reveals a hypertriglyceridemia in both beta3-deficient Chinese patients and mice and provides novel insights into the molecular mechanisms of the significant roles of beta3 in LPL secretion and triglyceride metabolism, drawing attention to the metabolic consequences in patients with beta3-deficient Glanzmann thrombasthenia. FAU - Xiao, Bing AU - Xiao B AD - From the State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, China (B.X., X.X.). FAU - Mao, Jianhua AU - Mao J AD - State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.M., W.Z., Y.W., P.W., Z.R., X.X.). FAU - Sun, Boyang AU - Sun B AD - State Key Laboratory of Experimental Hematology, National Clinical Research Center for Hematological Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (B.S., H.L., R.Y.). FAU - Zhang, Wei AU - Zhang W AD - State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.M., W.Z., Y.W., P.W., Z.R., X.X.). FAU - Wang, Yun AU - Wang Y AD - State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.M., W.Z., Y.W., P.W., Z.R., X.X.). FAU - Wang, Pengran AU - Wang P AD - State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.M., W.Z., Y.W., P.W., Z.R., X.X.). FAU - Ruan, Zheng AU - Ruan Z AD - State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.M., W.Z., Y.W., P.W., Z.R., X.X.). FAU - Xi, Wenda AU - Xi W AD - Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China (W.X.). FAU - Li, Huiyuan AU - Li H AD - State Key Laboratory of Experimental Hematology, National Clinical Research Center for Hematological Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (B.S., H.L., R.Y.). FAU - Zhou, Jingyi AU - Zhou J AD - Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China (J.Z., Y.L., Q.D., X.W.). FAU - Lu, Yide AU - Lu Y AD - Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China (J.Z., Y.L., Q.D., X.W.). FAU - Ding, Qiulan AU - Ding Q AD - Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China (J.Z., Y.L., Q.D., X.W.). FAU - Wang, Xuefeng AU - Wang X AD - Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China (J.Z., Y.L., Q.D., X.W.). FAU - Liu, Jingqiu AU - Liu J AD - Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China (J.L., C.L.). FAU - Yan, Jinsong AU - Yan J AD - Department of Hematology, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Second Hospital of Dalian Medical University, China (J.Y.). FAU - Luo, Cheng AU - Luo C AD - Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China (J.L., C.L.). FAU - Shi, Xiaofeng AU - Shi X AD - Department of Hematology, Affiliated Hospital of Jiangsu University, Zhenjiang, China (X.S.). FAU - Yang, Renchi AU - Yang R AD - State Key Laboratory of Experimental Hematology, National Clinical Research Center for Hematological Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (B.S., H.L., R.Y.). FAU - Xi, Xiaodong AU - Xi X AD - From the State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, China (B.X., X.X.). AD - State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.M., W.Z., Y.W., P.W., Z.R., X.X.). LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200402 PL - United States TA - Arterioscler Thromb Vasc Biol JT - Arteriosclerosis, thrombosis, and vascular biology JID - 9505803 RN - 0 (Biomarkers) RN - 0 (ITGB3 protein, human) RN - 0 (Integrin beta Chains) RN - 0 (Integrin beta3) RN - 0 (Multiprotein Complexes) RN - 0 (Triglycerides) RN - EC 2.7.10.- (protein kinase D) RN - EC 2.7.11.13 (Protein Kinase C) RN - EC 3.1.1.34 (LPL protein, human) RN - EC 3.1.1.34 (Lipoprotein Lipase) SB - IM MH - Adolescent MH - Animals MH - Biomarkers/blood MH - Case-Control Studies MH - Child MH - China MH - Disease Models, Animal MH - Female MH - Genetic Predisposition to Disease MH - Humans MH - Hypertriglyceridemia/blood/diagnosis/enzymology/*etiology MH - Integrin beta Chains/genetics/*metabolism MH - Integrin beta3/genetics/*metabolism MH - Lipoprotein Lipase/*blood MH - Male MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Multiprotein Complexes MH - Mutation MH - Protein Binding MH - Protein Interaction Domains and Motifs MH - Protein Kinase C/metabolism MH - Risk Factors MH - Thrombasthenia/blood/*complications/diagnosis/genetics MH - Triglycerides/*blood OTO - NOTNLM OT - integrins OT - lipoprotein lipase OT - lipoproteins OT - protein kinase D OT - thrombasthenia EDAT- 2020/04/03 06:00 MHDA- 2020/07/15 06:00 CRDT- 2020/04/03 06:00 PHST- 2020/04/03 06:00 [pubmed] PHST- 2020/07/15 06:00 [medline] PHST- 2020/04/03 06:00 [entrez] AID - 10.1161/ATVBAHA.119.313191 [doi] PST - ppublish SO - Arterioscler Thromb Vasc Biol. 2020 May;40(5):1296-1310. doi: 10.1161/ATVBAHA.119.313191. Epub 2020 Apr 2.