The objectives of this analysis are to re-examine the foundational studies of the in vivo metabolism of plasma LDL (low-density lipoprotein) particles in humans and, based on them, to reconstruct our understanding of the governance of the concentration of plasma LDL and the maintenance of cholesterol homoeostasis in the hepatocyte. We believe that regulation of cholesterol homoeostasis within the hepatocyte is demonstrably more complex than envisioned by the LDL receptor paradigm, the conventional model to explain the regulation of plasma LDL and the fluxes of cholesterol into the liver, a model which was generated in the fibroblast but has never been fully validated in the hepatocyte. We suggest that the LDL receptor paradigm should be reconfigured as the apoB (apolipoprotein B) paradigm, which states that the rate at which LDL particles are produced is at least an important determinant of their concentration in plasma as the rate at which they are cleared from plasma and that secretion of cholesterol within VLDL (very-low-density lipoprotein) particles is an important mechanism of maintaining cholesterol homoeostasis within the hepatocyte. These two paradigms are not mutually exclusive. The LDL receptor paradigm, however, includes only one critical aspect of the regulation of plasma LDL, namely the rate at which LDL particles are cleared through the LDL receptor pathway, but ignores another – the rate at which LDL particles are added to the plasma compartment. The apoB paradigm includes both and points to a different model of how the hepatocyte achieves cholesterol homoeostasis in a complex metabolic environment.
On the basis of a high correlation, non-HDL-C (non-high-density lipoprotein cholesterol) and apoB (apolipoprotein B) have been suggested to be of equivalent value for clinical practice; however, the strength of this relationship has not been examined in detail in patients with dyslipidaemia. The present study examines the variance of non-HDL-C compared with apoB in 1771 consecutive patients evaluated in a lipid clinic. These patients were divided into normolipidaemic subjects ( n =407), type I hyperlipoproteinaemia ( n =16), type IIa ( n =736) and IIb ( n =231) hyperlipoproteinaemia, type III hyperlipoproteinaemia ( n =38), type IV hyperlipoproteinaemia ( n =509) and type V hyperlipoproteinaemia ( n =101). The relationship between non-HDL-C and apoB was examined both in terms of correlation and concordance. Correlation was high, but concordance was only moderate in the normolipidaemic subjects and in those with type IIa and type IIb hyperlipoproteinaemia. Correlation and concordance were both low in the subgroups with type III and type V hyperlipoproteinaemia. In those with type IV hyper-lipoproteinaemia, correlation was moderately high ( r =0.74), but concordance was only fair. In conclusion, our results indicate that there is substantial variance of apoB for given values of non-HDL-C in many dyslipidaemic subjects. It follows that correlation is not adequate as a sole judge of equivalence of laboratory parameters.