Abstract
The aim of this study was to evaluate whether soluble factors in plasma of familial combined hyperlipidemia (FCHL) patients affect hepatic protein secretion. Cultured human hepatocytes, i.e., HepG2 cells, were incubated with fasting plasma (20%, v/v, in DMEM) from untreated FCHL patients or normolipidemic controls. Overall protein secretion was 10-15% higher after incubation with FCHL plasma. This was specifically caused by an increase in four secreted proteins, with estimated sizes of 240, 180, 120, and <40 kD (P < 0.001, P < 0.006, P < 0.002, P < 0.02, respectively). The 240 kD protein in the secretion proteome was identified as fibronectin by mass spectrometry. Plasma fibronectin concentrations were elevated in FCHL patients, confirming biological relevance of these data. Overall protein secretion by HepG2 cells correlated with concentrations of triglycerides (r = 0.61, P < 0.001) in the applied plasma samples. VLDL+IDL isolated from FCHL patients, induced a higher protein secretion than lipoproteins isolated from controls (P < 0.001). Remarkably, secretion of apoB, the structural protein of VLDL, was stimulated to a similar extent by FCHL and control plasma. FCHL plasma did not induce excess secretion of apoB by HepG2 cells compared with control plasma. FCHL plasma did stimulate secretion of several distinct hepatic proteins, among which fibronectin was identified.
Highlights
The aim of this study was to evaluate whether soluble factors in plasma of familial combined hyperlipidemia (FCHL) patients affect hepatic protein secretion
The aim of the present study was to determine whether plasma from FCHL patients differed from control plasma in its capability to increase hepatic protein or lipoprotein secretion
The data demonstrated that FCHL plasma stimulated secretion of newly synthesized proteins from HepG2 cells to a significantly higher extent than control plasma
Summary
The aim of this study was to evaluate whether soluble factors in plasma of familial combined hyperlipidemia (FCHL) patients affect hepatic protein secretion. Available data on the direct effects of increased FFA fluxes on hepatic apoB production in normal human subjects are limited and apparently conflicting [2, 3] These data do not yet allow defenitive conclusions on the hepatic abnormality in FCHL. The scarce availability of hepatocytes from human FCHL patients renders it not feasible to directly study the role of the liver-specific pathways in FCHL in vitro. It is presently unresolved whether the hepatic hypersecretion of lipoproteins that is observed in FCHL is a process inherent to metabolic abnormalities in the liver, or may be driven by soluble factors (for instance fatty acids or cytokines) in FCHL plasma, or both.
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