PMID- 33883138
OWN - NLM
STAT- MEDLINE
DCOM- 20220418
LR  - 20220418
IS  - 2375-2548 (Electronic)
IS  - 2375-2548 (Linking)
VI  - 7
IP  - 17
DP  - 2021 Apr
TI  - Nuclear receptors FXR and SHP regulate protein N-glycan modifications in the 
      liver.
LID - 10.1126/sciadv.abf4865 [doi]
LID - eabf4865
AB  - Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) 
      are key regulators of metabolism. Here, we report a previously unknown function 
      for the hepatic FXR-SHP axis in controlling protein N-linked glycosylation. 
      Transcriptome analysis in liver-specific Fxr-Shp double knockout (LDKO) livers 
      revealed induction of genes encoding enzymes in the N-glycosylation pathway, 
      including Mgat5, Fut8, St3gal6, and St6gal1 FXR activation suppressed Mgat5, 
      while Shp deletion induced St3gal6 and St6gal1 Increased percentages of 
      core-fucosylated and triantennary glycan moieties were seen in LDKO livers, and 
      proteins with the "hyperglycoforms" preferentially localized to exosomes and 
      lysosomes. This up-regulation of N-glycosylation machinery was specific to the 
      Golgi apparatus and not the endoplasmic reticulum. The increased glycan 
      complexity in the LDKO correlated well with dilated unstacked Golgi ribbons and 
      alterations in the secretion of albumin, cholesterol, and triglycerides. Our 
      findings demonstrate a role for the FXR-SHP axis in maintaining glycoprotein 
      diversity in the liver.
CI  - Copyright (c) 2021 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 
      (CC BY-NC).
FAU - Mathur, Bhoomika
AU  - Mathur B
AUID- ORCID: 0000-0001-7146-1072
AD  - Department of Molecular and Integrative Physiology, University of Illinois at 
      Urbana-Champaign, Urbana, IL, USA.
FAU - Shajahan, Asif
AU  - Shajahan A
AUID- ORCID: 0000-0002-4804-1130
AD  - Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
FAU - Arif, Waqar
AU  - Arif W
AUID- ORCID: 0000-0002-9252-0200
AD  - Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 
      IL, USA.
FAU - Chen, Qiushi
AU  - Chen Q
AD  - Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
FAU - Hand, Nicholas J
AU  - Hand NJ
AUID- ORCID: 0000-0002-8172-1816
AD  - Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Abramowitz, Lara K
AU  - Abramowitz LK
AD  - Laboratory of Cell and Molecular Biology, National Institute of Diabetes and 
      Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
FAU - Schoonjans, Kristina
AU  - Schoonjans K
AUID- ORCID: 0000-0003-1247-4265
AD  - Ecole polytechnique federale de Lausanne, 1015 Lausanne, Switzerland.
FAU - Rader, Daniel J
AU  - Rader DJ
AUID- ORCID: 0000-0002-9245-9876
AD  - Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Kalsotra, Auinash
AU  - Kalsotra A
AUID- ORCID: 0000-0002-1011-0006
AD  - Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 
      IL, USA.
FAU - Hanover, John A
AU  - Hanover JA
AUID- ORCID: 0000-0002-3154-9878
AD  - Laboratory of Cell and Molecular Biology, National Institute of Diabetes and 
      Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
FAU - Azadi, Parastoo
AU  - Azadi P
AD  - Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
FAU - Anakk, Sayeepriyadarshini
AU  - Anakk S
AUID- ORCID: 0000-0003-2819-695X
AD  - Department of Molecular and Integrative Physiology, University of Illinois at 
      Urbana-Champaign, Urbana, IL, USA. anakk@illinois.edu.
AD  - Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, 
      IL, USA.
LA  - eng
GR  - R01 AA010154/AA/NIAAA NIH HHS/United States
GR  - R21 HD104039/HD/NICHD NIH HHS/United States
GR  - R01 DK114291/DK/NIDDK NIH HHS/United States
GR  - R01 HL134853/HL/NHLBI NIH HHS/United States
GR  - R01 HL109489/HL/NHLBI NIH HHS/United States
GR  - F30 DK108567/DK/NIDDK NIH HHS/United States
GR  - R24 GM137782/GM/NIGMS NIH HHS/United States
GR  - R01 DK113080/DK/NIDDK NIH HHS/United States
GR  - S10 OD018530/OD/NIH HHS/United States
GR  - R01 HL126845/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210421
PL  - United States
TA  - Sci Adv
JT  - Science advances
JID - 101653440
RN  - 0 (Polysaccharides)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Cholesterol/metabolism
MH  - *Liver/metabolism
MH  - Polysaccharides/metabolism
MH  - *Receptors, Cytoplasmic and Nuclear/genetics/metabolism
MH  - Transcriptional Activation
PMC - PMC8059921
EDAT- 2021/04/23 06:00
MHDA- 2022/04/19 06:00
PMCR- 2021/04/21
CRDT- 2021/04/22 06:02
PHST- 2020/10/30 00:00 [received]
PHST- 2021/03/04 00:00 [accepted]
PHST- 2021/04/22 06:02 [entrez]
PHST- 2021/04/23 06:00 [pubmed]
PHST- 2022/04/19 06:00 [medline]
PHST- 2021/04/21 00:00 [pmc-release]
AID - 7/17/eabf4865 [pii]
AID - abf4865 [pii]
AID - 10.1126/sciadv.abf4865 [doi]
PST - epublish
SO  - Sci Adv. 2021 Apr 21;7(17):eabf4865. doi: 10.1126/sciadv.abf4865. Print 2021 Apr.