Nuclear receptors FXR and SHP regulate protein N-glycan modifications in the liver

Abstract

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.

Identification of indocyanine green as a STT3B inhibitor against mushroom α-amanitin cytotoxicity

“…To test the inhibitory effect of ICG on protein glycan synthesis in animals, we performed lectin staining to assess in vivo glycation. We applied fluorescein-sambucus nigra agglutinin (SNA) and fluorescein-phaseolus vulgaris leucoagglutinin (PHA-L) to stain sialylated glycans and complex glycans, respectively, as previously reported 56 . As expected, SNA and PHA-L can label the glycated proteins localizing on the plasma membrane of liver cells.…”

Bile acids-gut microbiota crosstalk contributes to the improvement of type 2 diabetes mellitus

“…The SHP reduced hepatic lipid synthesis by inhibiting the expression of the transcription factor sterol regulatory element binding transcription factor-1c (SREBP-1c) and its downstream hepatic lipid synthesis genes ( Ahmad and Haeusler, 2019 ). In addition, the expression of SHP can also reduce hepatic gluconeogenesis by inhibiting phosphoenolpyruvate carboxykinase and fructose bisphosphatase-1 ( Mathur et al, 2021 ). Compared to wild-type mice, the fasting glucose tolerance was significantly impaired in FXR knockout (FXR KO) mice.…”

Clinical Aspects of Gut Microbiota in Hepatocellular Carcinoma Management

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