Regulation of Dietary Cholesterol Balance--A New Approach for Novel Cholesterol-Lowering Agents

iHumans.com <http://ihumans.com>

5 January, 2001

Regulation of Dietary Cholesterol Balance--A New Approach for Novel Cholesterol-Lowering Agents

Atherosclerosis is responsible for a large number of deaths in developed countries. It arises from complex causes involving genetic and nutritional factors. Nutritional factors are emphasized, and atherosclerosis is usually the end result of hyperlipidemia, commonly known as high cholesterol in the blood. Thus atherosclerosis may be referred to as a disease from contemporary life style. Such disease conditions arising from nutritional factors are rapidly increasing in the number of patients.

Atherosclerosis and hyperlipidemia offer pharmaceutical industry major targets for the drug development. Worldwide sales of cholesterol-reducing drugs will grow by 7.5% per year reaching US$16 billions by 2007. Hyperlipidemia is treated by statins. Statins have been shown to reduce total mortality in patients with established coronary artery disease and to prevent the onset of a first coronary event in patients without coronary artery disease. Statins are excellent drugs as evidenced from the market acceptance. The global market for cholesterol-reducing and triglyceride-reducing drugs totaled $7.7 billion in 1997, with statin sales of $6.7 billion, and statins accounted for 94% of sales of cholesterol-reducing drugs in the United States during 1997. Statin segment of anti-atherosclerosis will increase its share of the cholesterol-reducing market during the next 10 years, as the patent protection ends in 2007.

Statins are small molecular drugs that inhibit an enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), involved in the biosynthesis of cholesterol in the body. Cholesterol is an essential component of the cell and nearly 70% are made in the body while the rest is taken from the food. Therefore, it would be better to develop drugs that do not inhibit the synthesis of cholesterol in the body but help keep the normal level by adjusting the in- and out-transport of cholesterol from the cell. This would be particularly suitable when cholesterol is excessively taken from the fatty food. Intensive investigation is beginning for a proof of this concept and drug development in the pharmaceutical industry.

Modern concepts of biomedicine lead to new venues for drug development. One of them is the remarkable development made in recent years in the area of nuclear receptors. There are a large number of receptors in the nucleus of the cell that receive signals carried by small molecules (ligands) from outside to induce specific cell functions. Hormones and their receptors are an example. There are a number of nuclear receptors whose ligands are not known thus referred to as "orphan" receptors. Thanks to intensive research, these orphans are getting legitimized, and revealed functions are extremely interesting, and important particularly for the mechanistic characterizations of cholesterol balance and occurrence of hyperlipidemia.

Nuclear receptors form dimeric complexes with the particular nuclear receptor partner termed RXR to be active for the induction of specific gene functions. A few of the dimeric receptor complexes have been delineated to the physiological activities related to the regulation of cholesterol levels. For example, a nuclear receptor LXR forms RXR/LXR to induce ABC1 reverse transporter of cholesterol to pump out cellular cholesterol, resulting in lowering dietary cholesterol. Still another nuclear receptor FXR forms RXR/FXR to induce cytochrome P450 hydroxylase CYP7A1 that metabolizes cholesterol to bile acid to again lower cholesterol level. Small molecular ligands that specifically bind to each nuclear receptor are now hotly pursued in an aim to develop novel drugs against hyperlipidemia. These ligands are mostly analogs of RXR compounds that bind to and activate RXR.

Regulation of Dietary Cholesterol Balance
Some nuclear receptors are involved in lipid metabolism. As they form obligate heterodimers with retinoid X receptors (RXRs), they are activated by RXR agonists (rexinoids). These receptors, namely oxysterol receptors (LXRs, liver x receptors) and bile acid receptors (FXRs), are also activated by their own selective agonists. With the use of LXR-selective agonists, it has been shown recently that RXR/LXR upregulates the expression of reverse transporter of cholesterol, ABC1 (ATP-binding cassette transporter 1) in peripheral tissues, including macrophages (Repa JJ et al, 2000: uid= 10968783). The importance of reverse cholesterol transporters is suggested in a rare human genetic disease "sitosterolemia". This inherited disorder has mutations in ABCG5 and ABCG8 genes and is characterized by hyperabsorption of plant sterols (sitosterol, stigmasterol, and campesterol) and of cholesterol (Berge KE, 2000: uid=11099417). Individuals with this disease have high plasma levels of dietary cholesterol, and develop xanthomas (cholesterol deposits in skin and tendons) and coronary atherosclerosis at an early age. As ABCG5 and ABCG8 genes encode proteins with homology to ABC1, sitosterolemic patients appear to lack a gene product that normally limits the absorption and accelerates the biliary excretion of sterols. In another line of related evidence, ABCA1 of the same gene family was found to be mutated in Tangier disease characterized by defective efflux of cholesterol from cells, resulting in a severe HDL deficiency syndrome (Oram JF et al, 2000: uid=10882340).

When FXR is activated by its selective agonists, hydroxylase CYP7A1 is induced to a large extent. CYP7A1 is rate-limiting in the biosynthesis of bile acids from cholesterol. Additional evidence follows in recent literature on regulation of cholesterol balance. Apolipoprotein E (apoE) is secreted by macrophages in the artery wall, and exerts an important protective effect against the development of atherosclerosis. Previous studies indicate that increases in cellular free cholesterol levels stimulate apoE transcription in macrophages and adipocytes. In fact, Laffitte BA et al (Proc. Natl. Acad. Sci. USA 98, 507-512: 2001) have reported recently that RXR/LXR heterodimers activated by LXR-selective ligands directly regulate apoE transcription through interaction with a conserved LXR response element present in both apoE gene enhancers ME.1 and ME.2 (Shih SJ et al, 2000: uid=10893248).

These findings, taken together with other reports, strongly suggest that activation of the LXR signaling pathway results in the up-regulation of ABC1 in peripheral cells to efflux free cholesterol for transport back to the liver, where it is converted to bile acids by the LXR-mediated increase in CYP7A1 expression. The end result should be serum cholesterol lowering and biliary excretion into feces. This mechanism of maintaining cholesterol balance would be superior to the inhibition of de novo synthesis of cholesterol by statins in that cellular cholesterol synthesis is maintained normally while dietary cholesterol is excreted to keep the requisite level.

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