Understanding the Essentials of Blood Lipid Metabolism

Kori J. Kingsbury, RN, MSN, Greg Bondy, MD, FRCPC

In This Article

The Pathways of Lipid Transport

There are three main pathways responsible for the generation and transport of lipids within the body. These pathways include the exogenous pathway, the endogenous pathway, and the pathway of reverse cholesterol transport.[7,17]

Following digestion and absorption of dietary fat, TG and cholesterol are packaged to form chylomicrons in the epithelial cells of the intestines. Chylomicrons circulate through the intestinal lymphatic system. In the blood, circulating chylomicrons interact at the capillaries of adipose tissue and muscle cells releasing TG to the adipose tissue to be stored and available for the body's energy needs. The enzyme LPL hydrolyzes the TG and free-fatty acids are released. Some of the components of the chylomicrons are "repackaged" into other lipoproteins, for example, some apolipoproteins are transferred to HDL, and the remaining chylomicron remnant particles are removed from the plasma by way of chylomicron remnant receptors present on the liver.

The endogenous pathway involves the liver synthesizing lipoproteins. TG and cholesterol ester are generated by the liver and packaged into VLDL particles and then released into the circulation. VLDL is then processed by LPL in tissues to release fatty acids and glycerol. The fatty acids are taken up by muscle cells for energy or by the adipose cells for storage. Once processed by LPL, the VLDL becomes a VLDL remnant. The majority of the VLDL remnants are taken up by the liver via the LDL receptor, and the remaining remnant particles become IDL, a smaller, denser lipoprotein than VLDL. The fate of some of the IDL particles requires them to be reabsorbed by the liver (again by the LDL receptor); however, other IDL particles are hydrolyzed in the liver by hepatic-triglyceride lipase to form LDL, a smaller, denser particle than IDL.

LDL is the main carrier of circulating cholesterol within the body, used by extra-hepatic cells for cell membrane and steroid hormone synthesis. Much of the LDL particles are taken up by LDL receptors in the liver; the remaining LDL is removed by way of scavenger pathways at the cellular level. As LDL is taken up by receptors, free cholesterol is released and accumulates within the cells. LDL receptor activity and uptake of LDL regulate plasma LDL concentration by several mechanisms, including decreasing the synthesis of hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase (which controls the rate of cholesterol synthesis), suppressing the synthesis of new LDL receptors in the cells, and activating the enzyme, acyl-coenzyme A cholesterol acyltransferase, which esterifies free cholesterol into cholesterol ester, storing cholesterol in the cell.[18]

Reverse cholesterol transport refers to the process by which cholesterol is removed from the tissues and returned to the liver.[19] HDL is the key lipoprotein involved in reverse cholesterol transport and the transfer of cholesteryl esters between lipoproteins.[20] The smallest and most dense lipoprotein particle is HDL. HDL is formed through a maturation process whereby precursor particles (nascent HDL) secreted by the liver and intestine proceed through a series of conversions (known as the "HDL cycle") to attract cholesterol from cell membranes and free cholesterol to the core of the HDL particle. There are subclasses of HDL particles, including HDL2 and HDL3. The exact mechanism by which the HDL delivers cholesterol esters to the liver is not well understood, but several mechanisms have been suggested. These include the action of cholesteryl ester transfer protein, which transforms HDL into a TG-rich particle that interacts with hepatic-triglyceride lipase. Cholesterol ester-rich HDL may also be taken up directly by the receptors in the liver. Another mechanism may be that cholesterol esters are delivered directly to the liver for uptake without catabolism of the HDL cholesterol particle.[19,21]

In the context of cardiovascular disease risk, it is established that higher levels of HDL are associated with lower levels of heart disease, therefore higher levels of HDL are considered to be protective.[22] In contrast, it is now appreciated that other lipoproteins, including VLDL, IDL, LDL, and the remnant particles rendered in lipid processing, are highly atherogenic. To reflect this, the term "non-HDL cholesterol" has been invoked to describe this increased risk reflected in the lipid profile that may not be otherwise identified by simply examining the LDL alone.[6] Non-HDL cholesterol therefore encompasses a broader indication of cardiovascular disease risk. This parameter is calculated by the equation {non-HDL cholesterol = total cholesterol - HDL}, and is an important consideration in ensuring that patients are treated appropriately to target levels.