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Wednesday, August 28, 2013

Lipid Metabolism and Sites of Action of Lipid-Modifying Drugs [Not Statins]

Lipid-modifying pharmacotherapies and their sites of action are indicated with red lines.

In the intestines, cholesterol arrives from the liver via the biliary system and from dietary sources.

Free cholesterol can be absorbed by Niemann-Pick C1-like 1 protein (NPC1L1) or eliminated from the body as bile salts.

Absorbed cholesterol is delivered to the liver in the form of chylomicrons, which contain apolipoprotein B‑48.

In the liver, cholesterol synthesized from free fatty acids or triglycerides is packaged and secreted as apolipoprotein B‑100-rich Very-Low-Density Lipoprotein (VLDL), in a process that requires the presence of Microsomal Triglyceride Transfer Protein (MTP).

Hydrolysis of VLDL results in the subsequent formation of Intermediate-Density Lipoprotein (IDL) and Low-Density Lipoprotein (LDL), both of which can be returned to the liver via the LDL receptor, or LDL can be deposited in macrophages within the arterial wall.

In the process of reverse cholesterol transport, specialized transporters and receptors facilitate the efflux of free cholesterol from peripheral macrophages to nascent High-Density Lipoprotein (HDL) and the HDL3 subfraction. Esterification of this cholesterol to cholesteryl esters produces mature HDL2, which either deposits its cholesterol load in the liver or is recycled to free apolipoprotein A‑I (apoA‑I).

Cholesteryl Ester Transfer Protein (CETP) connects HDL metabolism with the VLDL–IDL–LDL pathway, with VLDL exchanging triglycerides for cholesteryl esters from HDL.

Abbreviations: apoA‑I, apolipoprotein A‑I; apoB, apolipoprotein B; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDL‑R, LDL receptor; MTP, microsomal triglyceride transfer protein; NPC1L1, Niemann-Pick C1-like 1 protein; VLDL, very-low-density lipoprotein.