TY - JOUR
T1 - Nuclear receptors FXR and SHP regulate protein N-glycan modifications in the liver
AU - Mathur, Bhoomika
AU - Shajahan, Asif
AU - Arif, Waqar
AU - Chen, Qiushi
AU - Hand, Nicholas J.
AU - Abramowitz, Lara K.
AU - Schoonjans, Kristina
AU - Rader, Daniel J.
AU - Kalsotra, Auinash
AU - Hanover, John A.
AU - Azadi, Parastoo
AU - Anakk, Sayeepriyadarshini
N1 - Publisher Copyright:
© 2021 The Authors.
PY - 2021/4/21
Y1 - 2021/4/21
N2 - Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) are key regulators of metabo lism. 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 ac tivation 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 correlat ed well with dilated unstacked Golgi ribbons and alterations in the secretion of albumin, cholesterol, and tri glycerides. Our findings demonstrate a role for the FXR-SHP axis in maintaining glycoprotein diversity in the liver.
AB - Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) are key regulators of metabo lism. 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 ac tivation 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 correlat ed well with dilated unstacked Golgi ribbons and alterations in the secretion of albumin, cholesterol, and tri glycerides. Our findings demonstrate a role for the FXR-SHP axis in maintaining glycoprotein diversity in the liver.
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U2 - 10.1126/sciadv.abf4865
DO - 10.1126/sciadv.abf4865
M3 - Article
C2 - 33883138
AN - SCOPUS:85105018395
SN - 2375-2548
VL - 7
JO - Science Advances
JF - Science Advances
IS - 17
M1 - eabf4865
ER -