2000 George Lyman Duff Memorial Lecture - Atherosclerosis is a liver disease of the heart

The production of apolipoprotein B (apoB)-containing lipoproteins by the li ver is regulated by a complex series of processes involving apoB being cotr anslationally translocated across the endoplasmic reticulum and assembled i nto a lipoprotein particle. The translocation of apoB across the endoplasmi c reticulum is facilitated by the intraluminal chaperone, microsomal trigly ceride transfer protein (MTP). MTP facilitates the translocation and foldin g 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 M TP or sufficient lipid, apoB exhibits translocation arrest. Thus, apoB tran slation, translocation, and assembly with lipids to form a core-containing lipoprotein particle occur as concerted processes. Abrogation of greater th an or equal to1 of these processes diverts apoB into a degradation pathway that is dependent on conjugation with ubiquitin and proteolysis by the prot easome. The nascent core-containing lipoprotein particle that forms within the lumen of the endoplasmic reticulum can be "enlarged" to form a mature v ery low density lipoprotein particle. Additional studies show that the asse mbly and secretion of apoB-containing lipoproteins are linked to the choles terol/bile acid synthetic pathway controlled by cholesterol 7 alpha -hydrox ylase. Studies in cultured cells and transgenic mice indicate that the expr ession of cholesterol 7 alpha -hydroxylase indirectly regulates the express ion of lipogenic enzymes through changes in the cellular content of mature sterol response element binding proteins. Oxysterols and bile acids may als o act via the ligand-activated nuclear receptors LXR and FXR to link the me tabolic pathways controlling energy balance and lipid metabolism to nutriti onal state.