About Cholesteryl Ester Transfer Protein (CETP) Inhibition
CETP inhibition has multiple actions that are beneficial for CHD risk:
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Circulation
CETP inhibition blocks transportation of cholesterol esters from HDL > LDL, lowering LDL and increasing HDL
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Liver
CETP inhibition upregulates LDL catabolism in the liver by causing an increase in LDL receptors, resulting in drop in LDL levels in circulation
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Pancreas
CETP inhibition protects vital pancreatic B-cells by increasing small functional HDLs, supporting islet cell survival and increasing insulin production in the pancreas
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Brain
CETP inhibition promotes cholesterol clearance from the brain by increasing small functional HDLs that can cross the blood-brain barrier to clear out excess cholesterol, a precedent step to amyloid beta and tau accumulation
CETP Inhibition in the Pancreas
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Pancreas
CETP inhibition also protects vital pancreatic β cells
ApoE plays a central role in the transport of Aβ from the brain
CNS ApoE redistribute cholesterol and lipids to neurons and other brain cells for repair and remodeling of membranes, organelle biogenesis, and synaptogenesis. ApoE in addition to transporting lipids across organs in the periphery also regulates amyloid-β (Aβ) aggregation and clearance. In Alzheimer’s disease animal models, increasing ApoE lipidation by genetic or pharmacological methods improves Aβ clearance, reduces brain inflammation and improves cognition.
A marked (~80%) reduction in insoluble Aβ 1e42 in the hippocampus after intrahippocampal administration of APP.PS1/TRE4 mice 8 weeks after injection of the AAVrh.10-APOE2 vector. These data suggest that APOE2 can essentially counteract or reverse the ability of APOE4 to promote brain Ab accumulation and deposition/fibrillization
How does CETP inhibition fit into the Alzheimer’s story?
CETP activity is detected in cerebrospinal fluid especially in astrocytes
Close to senile plaques, intense staining of reactive astrocytes in gray matter was observed
CETP polymorphism modifies the AD risk associated with ApoE ε4 allele
It is hypothesized that CETP leads to delipidation of apoE-HDL with diminished function of the particle
High brain CETP concentration would result in low levels of HDL associated with high levels of neuronal cholesterol and an increased risk of AD
10 mg of obicetrapib significantly increases beneficial HDL indices