Ectopic expression of <i>N</i>‐acetylglucosaminyltransferase V accelerates hepatic triglyceride synthesis

Kamada, Y.; Ebisutani, Yusuke; Kida, Sachiho; Mizutani, Kayo; Akita, Maaya; Yamamoto, Akiko; Fujii, Hironobu; Sobajima, Tomoaki; Terao, Naoko; Takamatsu, Shinji; Yoshida, Yasuhiko; Takehara, Tetsuo; Miyoshi, Eiji

doi:10.1111/hepr.12541

Cited by 4 publications

(4 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These and our current results suggest HBP and N-glycan branching interact descriptively as a thrifty phenotype 52 . Moreover, Mgat5 transgenic mice displayed increased body-weight and liver to body-weight ratio 53 , along with increased hepatic lipogenesis characterized by elevated Fasn, Acc and Srebp-1 gene expression 54 . Conversely, Mgat5 −/− mice are resistant to weight-gain on 9% fat diet, and display hypersensitivity to fasting with greater glycogen depletion and hypoglycemia 19 , essentially an opposing phenotype compared to GlcNAc-supplemented wild-type mice in the present study.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Reprogramming by Hexosamine Biosynthetic and Golgi N-Glycan Branching Pathways

Ryczko

Pawling

Chen

et al. 2016

Sci Rep

View full text Add to dashboard Cite

De novo uridine-diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis requires glucose, glutamine, acetyl-CoA and uridine, however GlcNAc salvaged from glycoconjugate turnover and dietary sources also makes a significant contribution to the intracellular pool. Herein we ask whether dietary GlcNAc regulates nutrient transport and intermediate metabolism in C57BL/6 mice by increasing UDP-GlcNAc and in turn Golgi N-glycan branching. GlcNAc added to the drinking water showed a dose-dependent increase in growth of young mice, while in mature adult mice fat and body-weight increased without affecting calorie-intake, activity, energy expenditure, or the microbiome. Oral GlcNAc increased hepatic UDP-GlcNAc and N-glycan branching on hepatic glycoproteins. Glucose homeostasis, hepatic glycogen, lipid metabolism and response to fasting were altered with GlcNAc treatment. In cultured cells GlcNAc enhanced uptake of glucose, glutamine and fatty-acids, and enhanced lipid synthesis, while inhibition of Golgi N-glycan branching blocked GlcNAc-dependent lipid accumulation. The N-acetylglucosaminyltransferase enzymes of the N-glycan branching pathway (Mgat1,2,4,5) display multistep ultrasensitivity to UDP-GlcNAc, as well as branching-dependent compensation. Indeed, oral GlcNAc rescued fat accumulation in lean Mgat5−/− mice and in cultured Mgat5−/− hepatocytes, consistent with N-glycan branching compensation. Our results suggest GlcNAc reprograms cellular metabolism by enhancing nutrient uptake and lipid storage through the UDP-GlcNAc supply to N-glycan branching pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

Metabolic Reprogramming by Hexosamine Biosynthetic and Golgi N-Glycan Branching Pathways

Ryczko

Pawling

Chen

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

“…Briefly, recent genome-wide CRISPR screens in HAP1 cells revealed correlated essentiality between fatty acid synthase (FASN) and multiple N-glycosylation enzymes, indicating a role for ER and Golgi pathways in lipogenesis (19). Transgenic mice overexpressing either glutamine: fructose-6P-aminotransferase (Gfpt) in the HBP or Golgi Mgat5 in the liver display obesity, steatosis, impaired glucose tolerance and insulin resistance (20, 21). Conversely, Mgat5 deficient mice are resistant to weight gain on a high fat diet (22), similar in this regard to wild type mice on a high fat diet in which branched chain amino acids (BCAA: Leu, Ile, Val) have been reduced (23).…”

Section: Introductionmentioning

confidence: 99%

SLC3A2 N-glycosylation and alternate evolutionary trajectories for amino acid metabolism

Zhang

Shafaq-Zadah

Pawling

et al. 2022

Preprint

View full text Add to dashboard Cite

SLC3A2 (4F2hc, CD98) is an adaptor to the SLC7A exchangers and has undergone extensive repositioning of N-glycosylation sites with vertebrate evolution, presumably in synchrony with the species-specific demands of metabolism. The SLC3A2*SLC7A5 heterodimer imports essential amino acids (AA) and thereby stimulates mTOR signaling, while SLC3A2*SLC7A11 imports cystine required for glutathione synthesis and mitigation of oxidative stress. Analysis of SLC3A2 N-glycans revealed stable site-specific profiles of Golgi remodeling, apart from the conserved N365 site where branching and poly-N-acetylglucosamine content were sensitive to the insertion of lost ancestral sites and to metabolism. N-glycans at N381 and N365 stabilized SLC3A2 in the galectin lattice and opposed endocytosis, while N365 which is nearest the membrane, also promoted down-regulation by galectin-driven clathrin-independent endocytosis (glycolipid-lectin GL-Lect). This is the first report of both positive and negative regulation by galectin binding to N-glycans that are strategically positioned in the same membrane glycoproteins. Proteomics analysis in SLC3A2 mutant HeLa cells with induced re-expression of SLC3A2 as bait revealed the canonical non-N-glycosylated interactors, SLC7A5 and SLC7A11 exchangers, but also AA transporters that were dependent on SLC3A2 N-glycosylation, and are themselves, N-glycosylated AA/Na+ symporters (SLC7A1, SLC38A1, SLC38A2, SLC1A4, SLC1A5). The results suggest that the N-glycans on SLC3A2 regulate clustering of SLC7A exchangers with AA/Na+ symporters, thereby promoting Gln/Glu export-driven import of essential AA and cystine, with the potential to adversely impact redox balance. The evolution of modern birds (Neoaves) led to improved control of bioenergetics with the loss of genes including SLC3A2, SLC7A-5, -7, -8, -10, BCAT2, KEAP1, as well as duplications of SLC7A9, SLC7A11 and the Golgi branching enzymes MGAT4B and MGAT4C known to enhance affinities for galectins. Analyzing the fate of these and other genes in the down-sized genomes of birds, spanning ~10,000 species and >100 Myr of evolution, may reveal the mystery of their longevity with prolonged vitality.

show abstract

“…GnT-V promotes cancer metastasis by enhancing growth factor signaling, integrin function, and expression of certain kinds of proteases (17,31,32). Very recently, we found that enhancement of hepatic GnT-V activity accelerates triglyceride synthesis (14). We also reported that GnT-V suppressed nonalcoholic steatohepatitis (NASH) progression in a mouse NASH model (16).…”

mentioning

confidence: 99%

Hepatic aberrant glycosylation byN-acetylglucosaminyltransferase V accelerates HDL assembly

Kamada

Kida

Hirano

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

View full text Add to dashboard Cite

Glycosylation is involved in various pathophysiological conditions. N-Acetylglucosaminyltransferase V (GnT-V), catalyzing β1-6 branching in asparagine-linked oligosaccharides, is one of the most important glycosyltransferases involved in cancer and the immune system. Recent findings indicate that aberrant N-glycan structure can modify lipid metabolism. In this study, we investigated the effects of aberrant glycosylation by GnT-V on high-density lipoprotein cholesterol (HDL) assembly. We used GnT-V transgenic (Tg) mice and GnT-V Hep3B cell (human hepatoma cell line) transfectants. The study also included 96 patients who underwent medical health check-ups. Total serum cholesterol levels, particularly HDL-cholesterol (HDL-C) levels, were significantly increased in Tg vs. wild-type (WT) mice. Hepatic expression of apolipoprotein AI (ApoAI) and ATP-binding cassette subfamily A member 1 (ABCA1), two important factors in HDL assembly, were higher in Tg mice compared with WT mice. ApoAI and ABCA1 were also significantly elevated in GnT-V transfectants compared with mock-transfected cells. Moreover, ApoAI protein in the cultured media of GnT-V transfectants was significantly increased. Finally, we found a strong correlation between serum GnT-V activity and HDL-C concentration in human subjects. Multivariate logistic analyses demonstrated that GnT-V activity was an independent and significant determinant for serum HDL-C levels even adjusted with age and gender differences. Further analyses represented that serum GnT-V activity had strong correlation especially with the large-size HDL particle concentration. These findings indicate that enhanced hepatic GnT-V activity accelerated HDL assembly and could be a novel mechanism for HDL synthesis.

show abstract

Ectopic expression of N‐acetylglucosaminyltransferase V accelerates hepatic triglyceride synthesis

Cited by 4 publications

References 49 publications

Metabolic Reprogramming by Hexosamine Biosynthetic and Golgi N-Glycan Branching Pathways

Metabolic Reprogramming by Hexosamine Biosynthetic and Golgi N-Glycan Branching Pathways

SLC3A2 N-glycosylation and alternate evolutionary trajectories for amino acid metabolism

Hepatic aberrant glycosylation byN-acetylglucosaminyltransferase V accelerates HDL assembly

Contact Info

Product

Resources

About