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Non-enzymic glycation of collagen inhibits binding of oxidized low-density lipoprotein.

ABSTRACT: We have examined the effect of non-enzymic glycation of native soluble collagen, in solution or in gels, on binding of oxidized low-density lipoprotein (LDL). We found the following. (1) Glycation markedly inhibited binding of LDL. This is contrary to results previously reported; the difference may be attributable to the use of detergent- and heat-denatured collagen, covalently bound to agarose beads, in the earlier study. (2) With increased duration of glycation, collagen solution would not gel, and preformed gels dissolved. (3) [14C]Glucose bound to collagen gels dissociated slowly, even at pH 5, suggesting that it was not present as a Schiff's base; in addition, ketoamines, pentosidine and fluorescent advanced glycation products were not detectable in glycated collagen gels, although they accumulated in tendon collagen glycated under the same conditions. It is hypothesized that the difference in glycation effects between gel and tendon may be due to the strength of cross-linking before glycation: the increase in intermolecular distance in collagen fibrils which results from glycation disrupts the fibrils in gels, preventing binding of LDL and formation of glycation-dependent cross-links, whereas the extensive cross-linking in tendon maintains the intermolecular distances within a range which permits formation of glycation cross-links.

SUBMITTER: Kalant N

PROVIDER: S-EPMC1134417 | biostudies-other | 1993 Aug

REPOSITORIES: biostudies-other

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Project description:Background and aimsAs the incidence of nonalcoholic steatohepatitis (NASH) continues to rise, understanding how normal liver functions are affected during disease is required before developing novel therapeutics which could reduce morbidity and mortality. However, very little is understood about how the transport of proteins and cells from the liver by the lymphatic vasculature is affected by inflammatory mediators or during disease.MethodsTo answer these questions, we utilized a well-validated mouse model of NASH and exposure to highly oxidized low density lipoprotein (oxLDL). In addition to single cell sequencing, multiplexed immunofluorescence and metabolomic analysis of liver lymphatic endothelial cells (LEC)s we evaluated lymphatic permeability and transport both in vitro and in vivo.ResultsConfirming similarities between human and mouse liver lymphatic vasculature in NASH, we found that the lymphatic vasculature expands as disease progresses and results in the downregulation of genes important to lymphatic identity and function. We also demonstrate, in mice with NASH, that fluorescein isothiocyanate (FITC) dextran does not accumulate in the liver draining lymph node upon intrahepatic injection, a defect that was rescued with therapeutic administration of the lymphatic growth factor, recombinant vascular endothelial growth factor C (rVEGFC). Similarly, exposure to oxLDL reduced the amount of FITC-dextran in the portal draining lymph node and through an LEC monolayer. We provide evidence that the mechanism by which oxLDL impacts lymphatic permeability is via a reduction in Prox1 expression which decreases lymphatic specific gene expression, impedes LEC metabolism and reorganizes the highly permeable lymphatic cell-cell junctions which are a defining feature of lymphatic capillaries.ConclusionsWe identify oxLDL as a major contributor to decreased lymphatic permeability in the liver, a change which is consistent with decreased protein homeostasis and increased inflammation during chronic liver disease.

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Non-enzymic glycation of collagen inhibits binding of oxidized low-density lipoprotein.

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