Insights into apolipoprotein C metabolism from transgenic and gene-targeted mice

Studies in humans on the in vivo metabolism of apolipoprotein (apo) Cs have been hampered by the highly complex nature of lipoprotein metabolism, whic h can be influenced by multiple genetic and environmental factors, in order to gain new insights into the function of the individual apoCs in lipoprot ein metabolism, several laboratories have created mouse models lacking or o verexpressing the respective APOC genes through the technologies of gene ta rgeting and transgenesis. Until now, the only well-established in vivo meta bolic function of apoC-I has been its inhibitory action on the uptake of ve ry low-density lipoprotein (VLDL) via hepatic receptors, particularly the l ow-density lipoprotein (LDL) receptor-related protein. Consequently the pre sence of apoC-I on the lipoprotein particle may prolong its residence time in the circulation and subsequently facilitate its conversion to LDL. ApoC- II, on the other hand, is a major activator of lipoprotein lipase, which is required for an efficient processing of triglyceride-rich lipoproteins in the circulation. However; an excess of apoC-II on the lipoprotein particle has been suggested to inhibit the lipoprotein-lipase-mediated hydrolysis of triglycerides. From studies with APOC3 transgenic and ApoC3-knockout mice, it appears that apoC-III inhibits the lipolysis of triglyceride-rich lipop roteins by hampering the interaction of these lipoproteins with the heparan sulfate proteoglycan-lipoprotein lipase complex. Subsequently the poorly l ipolyzed apoC-III-containing lipoprotein particles may accumulate in plasma because of their lower binding affinity towards hepatic receptors due to a change in lipid composition, particle size or the presence of apoC-III on the particle itself From these data it can thus be concluded that ail C apo lipoproteins specifically modulate the metabolism of triglyceride-rich lipo proteins, which may contribute to the development of hyperlipidemia and oth er lipoprotein abnormalities in humans.