Hepatic uptake of chylomicron remnants.
Chylomicrons are formed in the intestine and transport dietary triglyceride to peripheral tissues and cholesterol to the liver. The enzyme lipoprotein lipase, with apolipoprotein (apo)C-II as a co-factor, hydrolyzes chylomicron triglyceride allowing the delivery of free fatty acids to muscle and adipose tissue. As a result, a new particle called a chylomicron remnant is formed. This particle is enriched in cholesteryl ester and fat-soluble vitamins and contains apoB-48 and apoE. It is rapidly removed from the circulation by the liver. ApoE is the moiety required for rapid hepatic removal. Its activity is inhibited by C apolipoproteins, especially apoC-I. Hepatic removal appears to be accomplished by several overlapping mechanisms. The particle must first achieve a size that allows it to be "sieved" through the endothelial fenestre allowing entrance into the space of Disse. Here, it may 1) be removed directly by LDL receptors; 2) acquire additional apoE that is secreted free into the space, and then be removed directly by the LDL receptor-related protein (LRP); or 3) it may be sequestered in the space. Sequestration occurs by binding of apoE to heparan sulfate proteoglycans and/or binding of apoB to hepatic lipase. Sequestered particles may be further metabolized allowing apoE, and lysophospholipid enrichment, followed by transfer to one of the above receptors for hepatic uptake. The above formulation is based upon animal studies. In humans, delayed removal of chylomicron remnants has been documented in diabetes, renal failure, and familial combined hyperlipemia and is the abnormality resulting in type III hyperlipidemia. Case control studies have identified delayed remnant removal as an independent risk factor for atherosclerotic cardiovascular disease. Thus, understanding the further details of the processes, and how it can be regulated in humans, is an important challenge for the future.
Cooper
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AD
Research Institute, Palo Alto Medical Foundation, CA 94301, USA.
D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism; D002914:Chylomicrons / Q000378:metabolism*; D006801:Humans; D008049:Lipase / Q000378:metabolism; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism*; D008954:Models, Biological; D010740:Phospholipases / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism
D001053:Apolipoproteins; D002914:Chylomicrons; D011509:Proteoglycans; D011973:Receptors, LDL; D010740:Phospholipases; D008049:Lipase