Box 213 Biochemistry In Medicine

ApoE Alleles Predict Incidence of Alzheimer's Disease

In the human population there are three common variants, or alleles, of the gene encoding apolipoprotein E. The most common, accounting for about 78% of human apoE alleles, is APOE3; alleles APOE4 and APOE2 account for 15% and 7%, respectively. The APOE4 allele is particularly common in humans with Alzheimer's disease, and the link is highly predictive. Individuals who inherit APOE4 have an increased risk of late-onset Alzheimer's disease. Those who are ho-mozygous for APOE4 have a 16-fold increased risk of developing the disease; for those who do, the mean age of onset is just under 70 years. For people who inherit two copies of APOE3, by contrast, the mean age of onset of Alzheimer's disease exceeds 90 years.

The molecular basis for the association between apoE4 and Alzheimer's disease is not yet known. Speculation has focused on a possible role for apoE in stabilizing the cytoskeletal structure of neurons. The apoE2 and apoE3 proteins bind to a number of proteins associated with neuronal microtubules, whereas apoE4 does not. This may accelerate the death of neurons. Whatever the mechanism proves to be, these observations promise to expand our understanding of the biological functions of apolipoproteins.

HDL may be taken up in the liver by receptor-mediated endocytosis, but at least some of the cholesterol in HDL is delivered to other tissues by a novel mechanism. HDL can bind to plasma membrane receptor proteins called SR-BI in hepatic and steroidogenic tissues such as the adrenal gland. These receptors mediate not endocytosis but a partial and selective transfer of cholesterol and other lipids in HDL into the cell. Depleted HDL then dissociates to recirculate in the bloodstream and extract more lipids from chylomicron and VLDL remnants. Depleted HDL can also pick up cholesterol stored in extrahepatic tissues and carry it to the liver, in reverse cholesterol transport pathways (Fig. 21-40). In one reverse transport path, interaction of nascent HDL with SR-BI receptors in cholesterol-rich cells triggers passive movement of cholesterol from the cell surface into HDL, which then carries it back to the liver. In a second pathway, apoA-I in depleted HDL in-

Michael Brown and Joseph Goldstein

teracts with an active transporter, the ABC1 protein, in a cholesterol-rich cell. The apoA-I (and presumably the HDL) is taken up by endocytosis, then resecreted with a load of cholesterol, which it transports to the liver.

The ABC1 protein is a member of a large family of multidrug transporters, sometimes called ABC transporters because they all have ATP-binding cassettes; they also have two transmembrane domains with six transmembrane helices (Chapter 11). These proteins actively transport a variety of ions, amino acids, vitamins, steroid hormones, and bile salts across plasma membranes. The CFTR protein that is defective in cystic fibrosis (see Box 11-3) is another member of this ABC family of multidrug transporters.

Cholesteryl Esters Enter Cells by Receptor-Mediated Endocytosis

Each LDL particle in the bloodstream contains apoB-100, which is recognized by specific surface receptor proteins, LDL receptors, on cells that need to take up cholesterol. The binding of LDL to an LDL receptor initiates endocytosis, which conveys the LDL and its receptor into the cell within an endosome (Fig. 21-42). The endosome eventually fuses with a lysosome, which contains enzymes that hydrolyze the cholesteryl esters, releasing cholesterol and fatty acid into the cytosol. The apoB-100 of LDL is also degraded to amino acids that are released to the cytosol, but the LDL receptor escapes degradation and is returned to the cell surface, to function again in LDL uptake. ApoB-100 is also present in VLDL, but its receptor-binding domain is not available for binding to the LDL receptor; conversion of VLDL to LDL exposes the receptor-binding domain of apoB-100. This pathway for the transport of cholesterol in blood and its receptor-mediated endocytosis by target tissues was elucidated by Michael Brown and Joseph Goldstein.

LDL particle r\i

LDL particle r\i

Nucleus

■ Amino Fatty acids

Cholesteryl acids ester droplet

FIGURE 21-42 Uptake of cholesterol by receptor-mediated endocytosis.

Lysosome

Nucleus

■ Amino Fatty acids

Cholesteryl acids ester droplet

FIGURE 21-42 Uptake of cholesterol by receptor-mediated endocytosis.

Lysosome

Cholesterol that enters cells by this path may be incorporated into membranes or reesterified by ACAT (Fig. 21-38) for storage within cytosolic lipid droplets. Accumulation of excess intracellular cholesterol is prevented by reducing the rate of cholesterol synthesis when sufficient cholesterol is available from LDL in the blood.

The LDL receptor also binds to apoE and plays a significant role in the hepatic uptake of chylomicrons and VLDL remnants. However, if LDL receptors are unavailable (as, for example, in a mouse strain that lacks the gene for the LDL receptor), VLDL remnants and chylomicrons are still taken up by the liver even though LDL is not. This indicates the presence of a back-up system for receptor-mediated endocytosis of VLDL remnants and chylomicrons. One back-up receptor is lipoprotein receptor-related protein (LRP), which binds to apoE as well as to a number of other ligands.

Cholesterol Biosynthesis Is Regulated at Several Levels

Cholesterol synthesis is a complex and energy-expensive process, so it is clearly advantageous to an organism to regulate the biosynthesis of cholesterol to complement dietary intake. In mammals, cholesterol production is regulated by intracellular cholesterol concentration and by the hormones glucagon and insulin. The rate-limiting step in the pathway to cholesterol (and a major site of regulation) is the conversion of HMG-CoA to mevalonate (Fig. 21-34), the reaction catalyzed by HMG-CoA reductase.

Regulation in response to cholesterol levels is mediated by an elegant system of transcriptional regulation of the gene encoding HMG-CoA reductase. This gene, along with more than 20 other genes encoding enzymes that mediate the uptake and synthesis of cholesterol and

Cytosol

Endoplasmic reticulum

Cytosol

Endoplasmic reticulum

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