PMID- 31668381
OWN - NLM
STAT- MEDLINE
DCOM- 20200526
LR  - 20200526
IS  - 2212-8778 (Electronic)
IS  - 2212-8778 (Linking)
VI  - 29
DP  - 2019 Nov
TI  - Roux-en-Y gastric bypass enhances insulin secretion in type 2 diabetes via 
      FXR-mediated TRPA1 expression.
PG  - 1-11
LID - S2212-8778(19)30558-7 [pii]
LID - 10.1016/j.molmet.2019.08.009 [doi]
AB  - OBJECTIVE: Roux-en-Y gastric bypass surgery (RYGB) improves the first phase of 
      glucose-stimulated insulin secretion (GSIS) in patients with type 2 diabetes. How 
      it does so remains unclear. Farnesoid X receptor (FXR), the nuclear receptor of 
      bile acids (BAs), is implicated in bariatric surgery. Moreover, the transient 
      receptor potential ankyrin 1 (TRPA1) channel is expressed in pancreatic beta-cells 
      and involved in insulin secretion. We aimed to explore the role of BAs/FXR and 
      TRPA1 in improved GSIS in diabetic rats after RYGB. METHODS: RYGB or sham surgery 
      was conducted in spontaneous diabetic Goto-Kakizaki (GK) rats, or FXR or TRPA1 
      transgenic mice. Gene and protein expression of islets were assessed by qPCR and 
      western blotting. Electrophysiological properties of single beta-cells were studied 
      using patch-clamp technique. Binding of FXR and histone acetyltransferase steroid 
      receptor coactivator-1 (SRC1) to the TRPA1 promoter, acetylated histone H3 (ACH3) 
      levels at the TRPA1 promoter were determined using ChIP assays. GSIS was measured 
      using enzyme-linked immunosorbent assays or intravenous glucose tolerance test 
      (IVGTT). RESULTS: RYGB increases GSIS, particularly the first-phase of GSIS in 
      both intact islets and GK rats in vivo, and ameliorates hyperglycemia of GK rats. 
      Importantly, the effects of RYGB were attenuated in TRPA1-deficient mice. 
      Moreover, GK beta-cells displayed significantly decreased TRPA1 expression and 
      current. Patch-clamp recording revealed that TRPA1(-/-) beta-cells displayed a 
      marked hyperpolarization and decreased glucose-evoked action potential firing, 
      which was associated with impaired GSIS. RYGB restored TRPA1 expression and 
      current in GK beta-cells. This was accompanied by improved glucose-evoked electrical 
      activity and insulin secretion. Additionally, RYGB-induced TRPA1 expression 
      involved BAs/FXR-mediated recruitment of SRC1, promoting ACH3 at the promoter of 
      TRPA1. CONCLUSIONS: The BAs/FXR/SRC1 axis-mediated restoration of TRPA1 
      expression plays a critical role in the enhanced GSIS and remission of diabetes 
      in GK rats after RYGB.
CI  - Copyright (c) 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.
FAU - Kong, Xiangchen
AU  - Kong X
AD  - Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, 
      Shenzhen 518060, PR China.
FAU - Tu, Yifan
AU  - Tu Y
AD  - Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, 
      Shenzhen 518060, PR China.
FAU - Li, Bingfeng
AU  - Li B
AD  - Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, 
      Shenzhen 518060, PR China.
FAU - Zhang, Longmei
AU  - Zhang L
AD  - Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, 
      Shenzhen 518060, PR China.
FAU - Feng, Linxian
AU  - Feng L
AD  - Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, 
      Shenzhen 518060, PR China.
FAU - Wang, Lixiang
AU  - Wang L
AD  - Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, 
      Shenzhen 518060, PR China.
FAU - Zhang, Lin
AU  - Zhang L
AD  - Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, 
      Shenzhen 518060, PR China.
FAU - Zhou, Huarong
AU  - Zhou H
AD  - Key laboratory of System Biology, Shanghai Institutes for Biological Sciences, 
      Chinese Academy of Sciences, Shanghai, PR China.
FAU - Hua, Xianxin
AU  - Hua X
AD  - Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, 
      Shenzhen 518060, PR China; University of Pennsylvania Perelman School of 
      Medicine, 421 Curie Blvd, Philadelphia, PA 19104, USA.
FAU - Ma, Xiaosong
AU  - Ma X
AD  - Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, 
      Shenzhen 518060, PR China. Electronic address: xsma@szu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190815
PL  - Germany
TA  - Mol Metab
JT  - Molecular metabolism
JID - 101605730
RN  - 0 (Histones)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (TRPA1 Cation Channel)
RN  - 0C5V0MRU6P (farnesoid X-activated receptor)
RN  - EC 2.3.1.48 (Nuclear Receptor Coactivator 1)
SB  - IM
MH  - Animals
MH  - Diabetes Mellitus, Type 2/metabolism/*pathology/surgery/veterinary
MH  - Evoked Potentials
MH  - Gastric Bypass
MH  - Histones/metabolism
MH  - *Insulin Secretion
MH  - Insulin-Secreting Cells/cytology/physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Nuclear Receptor Coactivator 1/antagonists & inhibitors/genetics/metabolism
MH  - Promoter Regions, Genetic
MH  - RNA Interference
MH  - RNA, Small Interfering/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Rats, Zucker
MH  - Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors/genetics/*metabolism
MH  - TRPA1 Cation Channel/genetics/*metabolism
PMC - PMC6728758
OTO - NOTNLM
OT  - Diabetes
OT  - FXR
OT  - Insulin secretion
OT  - RYGB
OT  - TRPA1
EDAT- 2019/11/02 06:00
MHDA- 2020/05/27 06:00
PMCR- 2019/08/15
CRDT- 2019/11/01 06:00
PHST- 2019/06/13 00:00 [received]
PHST- 2019/08/12 00:00 [revised]
PHST- 2019/08/12 00:00 [accepted]
PHST- 2019/11/01 06:00 [entrez]
PHST- 2019/11/02 06:00 [pubmed]
PHST- 2020/05/27 06:00 [medline]
PHST- 2019/08/15 00:00 [pmc-release]
AID - S2212-8778(19)30558-7 [pii]
AID - 10.1016/j.molmet.2019.08.009 [doi]
PST - ppublish
SO  - Mol Metab. 2019 Nov;29:1-11. doi: 10.1016/j.molmet.2019.08.009. Epub 2019 Aug 15.