2000 George Lyman Duff Memorial Lecture: atherosclerosis is a liver disease of the heart

The production of apolipoprotein B (apoB)-containing lipoproteins by the liver is regulated by a complex series of processes involving apoB being cotranslationally translocated across the endoplasmic reticulum and assembled into a lipoprotein particle. The translocation of apoB across the endoplasmic reticulum is facilitated by the intraluminal chaperone, microsomal triglyceride transfer protein (MTP). MTP facilitates the translocation and folding of apoB, as well as the addition of lipid to lipid-binding domains (which consist of amphipathic beta sheets and alpha helices). In the absence of MTP or sufficient lipid, apoB exhibits translocation arrest. Thus, apoB translation, translocation, and assembly with lipids to form a core-containing lipoprotein particle occur as concerted processes. Abrogation of >/=1 of these processes diverts apoB into a degradation pathway that is dependent on conjugation with ubiquitin and proteolysis by the proteasome. The nascent core-containing lipoprotein particle that forms within the lumen of the endoplasmic reticulum can be "enlarged" to form a mature very low density lipoprotein particle. Additional studies show that the assembly and secretion of apoB-containing lipoproteins are linked to the cholesterol/bile acid synthetic pathway controlled by cholesterol 7alpha-hydroxylase. Studies in cultured cells and transgenic mice indicate that the expression of cholesterol 7alpha-hydroxylase indirectly regulates the expression of lipogenic enzymes through changes in the cellular content of mature sterol response element binding proteins. Oxysterols and bile acids may also act via the ligand-activated nuclear receptors LXR and FXR to link the metabolic pathways controlling energy balance and lipid metabolism to nutritional state.