Deciphering Liver Glycome Regulation by the PGC-1/FN3K Axis

Introduction:
Diabetes in general, and specifically in the context of obesity, is characterized by hyperglycemia resulting in non-enzymatic glycation of proteins. Yet, the full scope of molecular targets for glycation, particularly in liver, is incompletely understood. De-glycation, which removes the attached sugars, is controlled intracellularly by fructosamine-3-kinase (FN3K). However, whether intracellular de-glycation is regulated in physiological contexts and what factors are involved in its regulation remain unknown.

Aim:
To identify factors controlling the regulation of FN3K and protein glycation in liver.

Methods:
Gene expression analysis in mouse liver and cell culture experiments with overexpression of the key metabolic regulators PGC-1s (PGC-1α and PGC-1β). Mass spectrometric analysis was used to monitor protein glycation.

Results:
Our data identify that regulation of protein glycation in liver is controlled by the key metabolic regulators PGC-1s in response to metabolic cues, particularly in the fed state. Liver-specific deletion of PGC-1s results in reduction of Fn3k expression and concomitant increase in specific protein glycation. In accordance, overexpression of PGC-1α in liver-derived cells induces Fn3k and reduction in protein glycation. Purification of glycated proteins followed by mass spectrometric analysis and subsequent validations reveal significant alterations in intracellular protein glycation in response to PGC-1α expression. Mechanistically, PGC-1α effect on Fn3k involves the activity of the transcription factor Foxo1.

Conclusions:
In liver, fasting and re-feeding govern intracellular protein glycation via PGC-1 dependent induction of FN3K. Our work reveals the scope and dynamic nature of the liver glycome, establishing the PGC1/FN3K axis as a key regulator of protein glycation.