Introduction Production of infectious HCV is dependent on hepatocytes VLDL assembly, maturation, and secretory machinery. ApoB-100 is the structural apolipoprotein of large VLDL (VLDL1), small VLDL2, and LDL. Although HCV production is dependent on VLDL, chronic HCV infection clinically manifests in lower VLDL and LDL levels, particularly in genotype 3.
Aim To determine the production and clearance rates of apoB and triglyceride (TG) in VLDL1 in chronic HCV infected patients compared to uninfected volunteers. In addition, to observe if altering the VLDL1 kinetics would affect low-density HCV RNA quantities.
Method VLDL1 kinetics were analysed using a protocol involving an IV infusion of a chylomicron-like lipid emulsion (Intralipid) for 120 min to prevent the clearance of VLDL1 by lipoprotein lipase.1 Multiple blood samples were taken during and for 4 h after the infusion. Lipoprotein kinetics were examined by cumulative flotation ultracentrifugation and the clearance of HCV RNA from different density fractions was studied by iodixanol gradient ultracentrifugation.2
Results VLDL1 TG production rate was lower for HCV patients [n=6] compared to healthy subjects1 [n=10], but the production rate of VLDL1 apoB was similar. Chronic HCV patients cleared Intralipid at a slower rate than uninfected controls.
Plasma HCV RNA accumulated linearly in the serum during the 6 h experiment [14% increase per hour], indicating that Intralipid infusion either stimulated virion production, diminished virion clearance or both. Immediately after the Intralipid infusion ceased, triglyceride cleared exponentially, but at a slower rate than in uninfected individuals. HCV RNA in a very-low density fraction (VLDF, d<1.025 g/ml) also immediately cleared, but linearly, parallelling VLDL1 clearance (t1/2=77 min). However, HCV RNA in the high density fraction continued to accumulate [19.8% increase per hr] during the post-infusion period.
Conclusion VLDL1 TG production and clearance rates are impaired in patients with chronic HCV infection. HCV associates with large TG-rich lipoproteins in vivo, and clears from the plasma via this route. However, competitive inhibition of lipoprotein clearance results in accumulation of HCV particles in the vascular compartment, particularly those that lack association with TG-rich lipoproteins. Intralipid effectively uncouples the interaction of higher density de novo produced particles, with VLDL. We hypothesise that HCV particles need to transfer onto very low density ‘acceptor’ particles to facilitate clearance via the remnant pathway.
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