PMID- 35167876
OWN - NLM
STAT- MEDLINE
DCOM- 20220506
LR  - 20220601
IS  - 1532-8600 (Electronic)
IS  - 0026-0495 (Linking)
VI  - 131
DP  - 2022 Jun
TI  - Deacetylation of Caveolin-1 by Sirt6 induces autophagy and retards high 
      glucose-stimulated LDL transcytosis and atherosclerosis formation.
PG  - 155162
LID - S0026-0495(22)00040-3 [pii]
LID - 10.1016/j.metabol.2022.155162 [doi]
AB  - BACKGROUND: Atherosclerosis (AS) is the basis of diabetic macrovascular 
      complications. The plasma low-density lipoprotein (LDL) particles transcytosis 
      across endothelial cells (ECs) and deposition under the endothelium is the 
      initiation step of AS. We previously reported that high glucose inhibits the 
      autophagic degradation of Caveolin-1 and promote LDL transcytosis across ECs, 
      which in turn accelerates atherosclerotic progression. Since Sirt6 is a 
      chromatin-associated protein with deacetylation activity, whether it can regulate 
      Caveolin-1 acetylation and regulating the autophagic degradation of Caveolin-1 
      remains elusive. METHODS: Autophagy and histone acetylation were assessed in the 
      umbilical cords of patients with gestational diabetes mellitus (GDM) by 
      immunohistochemistry. An in vitro model of LDL transcytosis was established, and 
      the role of Sirt6 in LDL transcytosis across endothelial cells was clarified. The 
      effect of Sirt6 on the autophagic degradation of Caveolin-1 under hyperglycemic 
      conditions was explored in a streptozotocin (STZ)-induced diabetic AS model 
      established using the ApoE(-/-) mice. RESULTS: Caveolin-1 and acetylated histone 
      H3 levels were significantly increased, while LC3B and Sirt6 were downregulated 
      in the monolayer of the vascular wall from GDM and type 2 diabetes mellitus 
      (T2DM) patients. Immunoprecipitation assays showed that Sirt6 interacts with 
      Caveolin-1 and specifically mediated its acetylation levels. Immuno-electron 
      microscopy (EM) further indicated that Sirt6 overexpression triggered the 
      autophagic lysosomal degradation of Caveolin-1. ECs-specific overexpression of 
      Sirt6 by adeno-associated viral vector serotype 9 (AAV9) induced autophagy, 
      reduced Caveolin-1 expression, and ameliorated atherosclerotic plaque formation 
      in STZ-induced diabetic ApoE(-/-) mice. CONCLUSION: Sirt6-mediated acetylation of 
      Caveolin-1 activates its autophagic degradation and inhibits high 
      glucose-stimulated LDL transcytosis. Thus, the Sirt6/Caveolin-1 autophagic 
      pathway plays a crucial role in diabetic AS, and the overexpression or activation 
      of Sirt6 is a novel therapeutic strategy.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Zhao, Ying
AU  - Zhao Y
AD  - Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 
      Hubei 430077, China.
FAU - Jia, Xiong
AU  - Jia X
AD  - Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 
      Hubei 430077, China.
FAU - Yang, Xiaoyan
AU  - Yang X
AD  - Department of Pharmacology, the Key Laboratory of Drug Target Researches and 
      Pharmacodynamics Evaluation of Hubei Province, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, Hubei 430030, China.
FAU - Bai, Xiangli
AU  - Bai X
AD  - Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 
      Hubei 430077, China.
FAU - Lu, Yajing
AU  - Lu Y
AD  - Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 
      Hubei 430077, China.
FAU - Zhu, Lin
AU  - Zhu L
AD  - Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 
      Hubei 430077, China.
FAU - Cheng, Wenzhuo
AU  - Cheng W
AD  - Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 
      Hubei 430077, China.
FAU - Shu, Meng
AU  - Shu M
AD  - Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 
      Hubei 430077, China.
FAU - Zhu, Yan
AU  - Zhu Y
AD  - Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 
      Hubei 430077, China.
FAU - Du, Xiaolong
AU  - Du X
AD  - Department of Thyroid Surgery, the First Affiliated Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, Zhejiang 310003, China.
FAU - Wang, Li
AU  - Wang L
AD  - Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 
      Hubei 430077, China.
FAU - Shu, Yan
AU  - Shu Y
AD  - Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 
      Hubei 430077, China.
FAU - Song, Yi
AU  - Song Y
AD  - Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 
      Hubei 430077, China.
FAU - Jin, Si
AU  - Jin S
AD  - Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 
      Hubei 430077, China. Electronic address: Jinsi@hust.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220212
PL  - United States
TA  - Metabolism
JT  - Metabolism: clinical and experimental
JID - 0375267
RN  - 0 (Apolipoproteins E)
RN  - 0 (Caveolin 1)
RN  - 0 (Lipoproteins, LDL)
RN  - EC 2.4.2.31 (Sirt6 protein, mouse)
RN  - EC 3.5.1.- (SIRT6 protein, human)
RN  - EC 3.5.1.- (Sirtuins)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Apolipoproteins E/metabolism
MH  - *Atherosclerosis/metabolism
MH  - Autophagy
MH  - Caveolin 1
MH  - *Diabetes Mellitus, Type 2/metabolism
MH  - Endothelial Cells/metabolism
MH  - Glucose/metabolism
MH  - Humans
MH  - Lipoproteins, LDL/metabolism/pharmacology
MH  - Mice
MH  - *Sirtuins/metabolism/pharmacology
MH  - Transcytosis
OTO - NOTNLM
OT  - Acetylation
OT  - Autophagic degradation
OT  - Caveolin-1
OT  - Diabetic atherosclerosis
OT  - LDL transcytosis
OT  - Sirt6
EDAT- 2022/02/16 06:00
MHDA- 2022/05/07 06:00
CRDT- 2022/02/15 20:12
PHST- 2021/11/24 00:00 [received]
PHST- 2022/01/20 00:00 [revised]
PHST- 2022/02/07 00:00 [accepted]
PHST- 2022/02/16 06:00 [pubmed]
PHST- 2022/05/07 06:00 [medline]
PHST- 2022/02/15 20:12 [entrez]
AID - S0026-0495(22)00040-3 [pii]
AID - 10.1016/j.metabol.2022.155162 [doi]
PST - ppublish
SO  - Metabolism. 2022 Jun;131:155162. doi: 10.1016/j.metabol.2022.155162. Epub 2022 
      Feb 12.