The investigators propose to investigate apolipoprotein B (apo B) biogenesis and apo B-containing lipoprotein particle formation. Apo B plays a major role in cholesterol transport. Hypercholesterolemia is a risk factor for atherosclerosis and coronary artery disease. Some patients with elevated serum cholesterol have a known defect in apo B structure. Many others have uncharacterized aberrations in metabolism of apo B containing lipoproteins, which may be related to defective assembly. An understanding of how these diverse lesions cause hyperlipoproteinemia will require detailed knowledge of the mechanism by which a normal lipoprotein particle is assembled and secreted. Yet, important features of lipoprotein particle assembly are poorly understood and not easily explained by current value of protein biogenesis and trafficking. Recently, the investigators have discovered unusual intermediates in the early events of apo B translocation across the endoplasmic reticulum membrane (see Preliminary Studies) by expression of cloned cDNAs encoding domains of apo B in both membrane-supplemented cell-free systems and in living cells. These intermediates will be characterized and related to stages in apo B-containing lipoprotein particle assembly, regulation and secretion. This analysis will be extended to later events in apo B biogenesis. Through these experiments a better understanding of apo B biogenesis and its relationship to lipoprotein particle formation will emerge. New insight into the mechanisms by which apo B may be post-translationally regulated under physiologic conditions and in hypercholesterolemic lipoprotein disorders of humans may follow.
| Hegde, R S; Voigt, S; Rapoport, T A et al. (1998) TRAM regulates the exposure of nascent secretory proteins to the cytosol during translocation into the endoplasmic reticulum. Cell 92:621-31 |
| Kivlen, M H; Dorsey, C A; Lingappa, V R et al. (1997) Asymmetric distribution of pause transfer sequences in apolipoprotein B-100. J Lipid Res 38:1149-62 |
| Hegde, R S; Lingappa, V R (1996) Sequence-specific alteration of the ribosome-membrane junction exposes nascent secretory proteins to the cytosol. Cell 85:217-28 |
| Chuck, S L; Lingappa, V R (1993) Analysis of a pause transfer sequence from apolipoprotein B. J Biol Chem 268:22794-801 |
| Chuck, S L; Lingappa, V R (1992) Pause transfer: a topogenic sequence in apolipoprotein B mediates stopping and restarting of translocation. Cell 68:9-21 |
