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Published on: April 26, 2019
High-fat diet alters N-glycosylation of PTPRJ in murine liver
Jannis Ulke1, Christian Schwedler2, Janine Krüger1
1Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Augustenburger Platz 1, 13353 Berlin, Germany; Charité - Universitätsmedizin Berlin, Max Rubner Center (MRC) for Cardiovascular Metabolic Renal Research, Berlin, Germany.
Abstract:
Protein tyrosine phosphatases (PTPs) regulate multiple signaling pathways. Disruption of tyrosine phosphorylation through imbalanced action between protein tyrosine kinases (RTKs) and PTPs is a hallmark of metabolic disorders, including insulin resistance. A representative member of the receptor-type PTP family, PTPRJ (DEP-1), was previously identified as a negative regulator of insulin signaling and possesses post-translational glycosylation sites. In this regard, it seems of great importance to decipher the structure of PTPRJ's glycosylation, particularly in the context of metabolic disturbances, but this has not been done in detail. Thus, here we aimed at characterizing the glycosylation pattern of PTPRJ in liver. We show that N-glycosylation accounts for up to half of PTPRJ's molecular weight. Applying mass spectrometry, we detected increased levels of high-mannose structures in PTPRJ in liver tissue of obese mice compared to lean littermates. In addition, complex neutral structures without fucose were also elevated in PTPRJ of high-fat diet (HFD) mice. Conversely, complex fucosylated N-glycans as well as sialylated bi- and triantennary N-glycans, were significantly reduced in PTPRJ of HFD-derived liver tissue compared to LFD by ∼two fold (P≤.01, P≤.0001 and P≤.001, respectively). In congruence with these findings, the mannosidase MAN2A1, responsible for the conversion of high-mannose to complex N-glycans, was significantly downregulated under HFD conditions. Here we present for the first time that HFD-induced obesity impacts on the glycosylation pattern of the insulin signaling component PTPRJ in liver. These findings may inspire new research on the glycosylation of PTPs in metabolic diseases and may open up new therapeutic approaches.
Insights
High-fat diet obesity alters protein tyrosine phosphatase PTPRJ glycosylation in the liver. These changes in N-glycans may link to insulin resistance and metabolic disorders.
Area of Science:
- Biochemistry
- Metabolic Signaling
- Glycobiology
Background:
- Protein tyrosine phosphatases (PTPs) are crucial regulators of cell signaling pathways.
- Imbalances in tyrosine phosphorylation, involving PTPs and protein tyrosine kinases, are implicated in metabolic disorders like insulin resistance.
- PTPRJ (DEP-1), a PTP family member, negatively regulates insulin signaling and has glycosylation sites, but its glycosylation pattern in metabolic disease is poorly understood.
Purpose of the Study:
- To characterize the N-glycosylation pattern of PTPRJ in the liver.
- To investigate how high-fat diet (HFD)-induced obesity affects PTPRJ glycosylation.
- To explore the potential link between altered PTPRJ glycosylation and metabolic disturbances.
Main Methods:
- Mass spectrometry-based glycomic analysis of PTPRJ from liver tissue of lean and obese mice on different diets.
- Quantification of various N-glycan structures (high-mannose, complex neutral, fucosylated, sialylated).
- Analysis of the expression of key glycosylation enzymes, such as MAN2A1.
Main Results:
- N-glycosylation constitutes a significant portion of PTPRJ's molecular weight.
- Obese mice (HFD) showed increased high-mannose and fucose-free complex neutral N-glycans on PTPRJ compared to lean controls.
- Conversely, complex fucosylated and sialylated N-glycans on PTPRJ were significantly reduced in HFD mice.
- The mannosidase MAN2A1, involved in N-glycan processing, was downregulated in HFD conditions.
Conclusions:
- This study provides the first evidence that HFD-induced obesity alters the liver PTPRJ glycosylation profile.
- Specific changes include an increase in high-mannose structures and a decrease in complex fucosylated and sialylated structures.
- These findings suggest a novel role for PTPRJ glycosylation in the pathophysiology of metabolic diseases and offer potential therapeutic targets.
