© 2001 American Heart Association, Inc.
Brief Review |
2000 George Lyman Duff Memorial Lecture
Atherosclerosis Is a Liver Disease of the Heart
From the Mammalian Cell and Molecular Biology Laboratory, San Diego State University, San Diego, Calif.
Correspondence to Roger A. Davis, Mammalian Cell and Molecular Biology Laboratory, Life Sciences Building LS307, 5500 Campanile Dr, San Diego State University, San Diego, CA 92182-4614. E-mail rdavis{at}sunstroke.sdsu.edu
Abstract—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 ß sheets and 
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 7-hydroxylase. Studies in cultured cells and
transgenic mice indicate that the expression of cholesterol
7-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.
Key Words: apolipoprotein B • lipoprotein assembly/secretion • cholesterol-7-hydroxylase • microsomal triglyceride transfer protein • ubiquitin-dependent proteasome degradation
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