PPG Title: New Approaches to Reduce Residual Cardiovascular Risk
SUMMARY/ABSTRACT
In the last 40 years, significant progress has been made in reducing cardiovascular events by lowering plasma
LDL-cholesterol (LDL-C). While statins and PCSK9 inhibitors effectively decrease LDL-C levels, significant
residual risk of CHD remains even in maximally treated individuals with low plasma levels of LDL-C.
Epidemiological and genetic studies suggest that a significant proportion of the residual risk is due to elevated
plasma levels of triglyceride-rich ApoB-Containing Lipoproteins (ApoBCLs). The three projects that comprise
this Program Project Grant (PPG) will elucidate new molecular mechanisms that regulate the synthesis,
secretion, and metabolism of ApoBCLs. Our PPG is comprised of distinguished investigators with a longstanding
history of collaboration, five of whom (Goldstein, Brown, Hobbs, Horton, and Cohen) have worked together for
25 years. In Project 1 of this new PPG, Radhakrishnan, Brown, and Goldstein have used an original and
innovative screening protocol to identify a cholesterol-mimetic small molecule that binds to Scap with high
specificity and blocks activation of SREBPs, the transcription factors that activate genes required for the
synthesis of cholesterol, fatty acids (FAs), and triglycerides (TGs). This compound will be used to elucidate the
molecular mechanism by which Scap senses sterols, enabling the first description of Scap’s cholesterol binding
site at atomic resolution. The current cholesterol mimetic compound and more potent derivatives in development
will be used to assess the clinical implications of a Scap inhibitor for reduction of plasma ApoBCLs. In Project
2, Horton, Kim, and Liang have identified a new lipogenic enzyme complex in liver. They will characterize
components of the FA synthesis complex and determine how this complex interacts with additional FA modifying
proteins and acyl-transferases required to synthesize TGs and ApoBCLs. Completion of the proposed studies
will identify new opportunities for therapeutic interventions to reduce the synthesis of FAs, TGs, and VLDL. In
Project 3, Hobbs and Cohen used population-based resequencing to identify loss-of-function mutations in
angiopoietin-like (ANGPTL) 3 and 8. They showed that mutations in either protein result in lower plasma LDL-
cholesterol and TG levels. Their studies will elucidate the mechanisms underlying the ApoBCL lowering effects
of ANGPTL3 and ANGPTL8. In the process, they will define a new pathway that promotes clearance of ApoBCLs
independently of the LDL receptor.
The Research Projects will be supported by three Cores: Administrative, Tissue Culture & Antibody Production,
and Mass Spectrometry.
Members of this PPG have a long record of collaborative interactions and exceptional productivity. We
will continue to focus on bold hypotheses designed to answer critical questions. The investigators take
special pride in publishing papers that are characterized by originality and scientific rigor. The
successful completion of our projects holds great promise for exposing new therapeutic opportunities
for the reduction of plasma ApoBCLs and residual cardiovascular risk.