Cholesteryl ester transfer protein ( CETP ) deficiency

HDL metabolism in cholesteryl ester transfer protein (CETP) deficiency

• genetic deficiency in CETP has been shown to be associated with exceptionally elevated levels of HDL-C and apo A-I, due to delayed catabolism of HDL
• this led to the concept that inhibition of CETP might be a pharmacologic strategy for raising HDL
• CETP Deficiency
  • It appears that factors regulating the exchange of high-density lipoprotein (HDL) cholesteryl ester (CE) with very-low-density lipoprotein (VLDL) triglycerides, and the subsequent catabolism of HDL triglycerides, play an important role in regulating HDL levels
  • CE transfer protein (CETP) facilitates the transfer of CEs among lipoproteins
  • deficiencies in the gene coding for CETP have been described
    • four different CETP gene mutations were reported in Japanese subjects. For example, a splicing defect, present in approximately 2% of the population, is a null mutation; homozygotes have markedly elevated levels of HDL-cholesterol (100-250 mg/dL) and of apolipoprotein (apo) AI
  • CETP deficiency results in delayed catabolism of CE in HDL and of apoA-I
    • this leads to the production of large HDL particles, enriched in CE
  • on review of the data, it would appear that CETP deficiency is associated with a reduced risk of atherosclerotic cardiovascular disease (5)

Reference:

1. Tall AR, Dammerman M, Breslow JL. Disorders of lipoprotein metabolism. In: Chien KR, ed. Molecular Basis of Cardiovascular Disease: A Companion to Braunwald's Heart Disease. Philadelphia: W.B. Saunders; 1999:413-427.
2. Tall AR. Plasma high density lipoproteins: metabolism and relationship to atherogenesis. J Clin Invest. 1990;86:379-384.
3. Tall AR. Plasma lipid transfer proteins. J Lipid Res. 1986;27:361-368.
4. Tall AR. Plasma lipid transfer proteins. Annu Rev Biochem. 1995;64:235-257.
5. Barter P. lecture presentation. HDL- mostly good - sometimes bad? American Diabetes Association Conference (June 10th 2006).