O-Glycoside Biomarker of Apolipoprotein C3: Responsiveness to Obesity, Bariatric Surgery, and Therapy with Metformin, to Chronic or Severe Liver Disease and to Mortality in Severe Sepsis and Graft vs Host Disease

Abstract

The glyco-isoforms of intact apolipoprotein C3 (ApoC3) were used to probe glycomic changes associated with obesity and recovery following bariatric surgery, liver diseases such as chronic hepatitis C (CHC) and alcoholic liver cirrhosis, as well as severe, multiorgan diseases such as sepsis and graft vs host disease (GVHD). ApoC3 glyco-isoform ratios responded to unique stimuli that did not correlate with serum lipids or with other blood components measured in either a control population or a group of extremely obese individuals. However, glyco-isoform ratios correlated with obesity with a 1.8-fold change among subjects eligible for bariatric surgery relative to a nonobese control population. Bariatric surgery resulted in rapid change of isoform distribution to that of nonobese individuals, after which the distribution was stable in each individual. Although multiple simultaneous factors complicated effector attribution, the isoform ratios of very obese individuals were nearly normal for diabetic individuals on metformin therapy. Glyco-isoform ratios were sensitive to liver diseases such as chronic hepatitis C and alcoholic liver cirrhosis. The correlation coefficient with fibrosis was superior to that of current assays of serum enzyme levels. Diseases of pregnancy that can result in liver damage, HELLP syndrome and pre-eclampsia, did not alter ApoC3 glyco-isoform ratios. Early after umbilical cord blood transplantation the isoform ratios changed and returned to normal in long-term survivors. Larger changes were observed in persons who died. GVHD had little effect. Persons with severe sepsis showed altered ratios. Similar cut-points for mortality (3.5-fold difference from controls) were found for UCBT and sepsis. Similar values characterized liver cirrhosis. Overall, while changes of glyco-isoform ratios occurred in many situations, individual stability of isoform distribution was evident and large changes were limited to high-level disease. If ratio changes associated with obesity are found to document a risk factor for long-term outcomes, the information provided by glyco-isoform ratio changes may provide important, novel information for diagnostic, prognostic and therapy response to metabolic conditions.

Quantitative analysis of intact apolipoproteins in human HDL by top-down differential mass spectrometry

“…These accurate mass fragment ions localized the O-glycosylation modification to the C-terminal end of this protein between the c 58 and c 77 ions (Asp 59 -Val 77 ) as shown in Fig. 5A, consistent with other findings showing Thr 74 to be the site of modification (36,37). Additionally, high-resolution threshold dissociation methods (i.e., CAD) revealed seven and three matching b and y fragment ions, respectively, with the predominant fragmentation being the selective removal of the sugar side chain (−291.09 Da, −656.20 Da), supporting the presence of an O-glycosylation modification (Fig.…”

Mass Spectrometric Identification of Aberrantly Glycosylated Human Apolipoprotein C-III Peptides in Urine from Schistosoma mansoni-infected Individuals

“…Changes in the ratio of apoC-III glyco-isoforms have also been demonstrated in other diseases (51). Moreover, changes in the glycosylation of (serum) proteins in general have been observed in a variety of liver diseases (52).…”

Structure of HDL: Particle Subclasses and Molecular Components

“…Moreover, a recent MS study of 96 serum samples showed that 30 % of the individuals displayed an apoC-III pattern with additional glycosylated variants, characterised by fucosylation (Nicolardi et al 2013b). The relevance of these glycosylated non-sialylated variants of apoC-III, as of the C-terminal truncated forms, is yet unclear, but may explain somewhat contradictory results showing higher relative levels of non-and lesssialylated apoC-III in obese subjects than in lean subjects (Harvey et al 2009;Karlsson et al 2009), although obesity is generally associated with high triglyceride levels.…”