Nuclear Receptors as Potential Therapeutic Targets for Metabolic Diseases

Metabolic syndrome is a collection of obesity-related metabolic dysfunctions, including hyperlipidemia, decreased HDL-c, insulin resistance, hypertension, and atherosclerosis. Given their roles in regulating key metabolic pathways, nuclear hormone receptors are current and prospective drug targets to treat these diseases. One reason for the success of nuclear receptor targeted drugs is their ability to have a robust effect on a pathway due to the regulation of multiple target genes within that pathway. Of course the multifaceted effects of nuclear hormone receptors can also be a drawback, when undesirable side effects are the result.

Cholesterol has earned a reputation as the malefactor of atherosclerosis and is a central target of many atherosclerosis reducing drugs, such as statins which inhibit HMG-CoA reductace, the enzyme that catalyzes the rate limiting step in cholesterol synthesis. In addition to reducing total cholesterol, it is desirable to increase the number of HDL particles, which serve as cholesterol janitors removing excess cholesterol from peripheral tissues. The most important class of cholesterol to reduce is LDL cholesterol, especially, smaller LDL particles, which enter to intima more easily and are more susceptible to oxidation.17,125,174 An attractive target for reducing cholesterol is LXR, a receptor that has evolved to protect the liver from cholesterol overload. An LXR agonist could increase bile acid export from the liver and reduce cholesterol absorption in the gut, thereby reducing total cholesterol.172,194 LXR also suppresses macrophage foam cell formation through increased cholesterol efflux and HDL-c (discussed below).169 One of the concerns over using LXR agonists in humans is the differential regulation of Cyp7a and CETP. In humans, LXR does not suppress Cyp7a while inducing the expression of CETP, which removes cholesterol from the anti-atherogenic HDL and transfers it to the pro-atherogenic VLDL.27,106,127 The greatest disadvantage of LXR agonism is increased lipogenesis, which may result in steatosis and increased TG levels.136 Since LXRbeta plays a minor role in the liver, a selective LXRbeta agonist may not cause steatosis. Alternatively, an intestinal selective agonist may reduce cholesterol absorption and protect from atherosclerosis.

Both FXR agonists and antagonists have been proposed as potential cholesterol lowering drugs. An FXR antagonist is desirable to increase the conversion of cholesterol into bile acids, a pathway that is inhibited by FXR.52,105 However, FXR stimulation by an agonist would increase bile acid export and excretion, thereby reducing total cholesterol.7 The FXR knockout mouse indicates that FXR antagonism may have undesirable side effects, such as development of fatty liver and insulin resistance, while FXR agonism may have the opposite desirable affects: lowering circulating lipid levels and increasing insulin sensitivity.23,195

Lowering TG and fatty acids is an important factor in treating the dyslipidemia that often leads to insulin resistance.24 The PPARs are master regulators of fatty acid metabolism and are therefore very attractive therapeutic targets for treating hypertriglyceridemia. Fibrates, drugs that are already in use for the treatment of dislipidemia, stimulate PPARalpha, which results in increased fatty acid oxidation and reduced fatty acid synthesis.179

Fatty acid oxidation, especially in muscle may also be increased by PPARdelta.120 Results in mice indicate that activation of PPARdelta protects from obesity.107 Although this effect has not been observed in primate studies, epidemiological studies have shown a correlation between obesity and certain nucleotide polymorphisms in PPARdelta.154, 156 A robust increase in HDL-c has been seen in primate studies, indicating that PPARdelta activation may also have beneficial effects on improving lipoprotein profile and suppressing atherosclerotic lesion progression.128,180 Synthetic PPARdelta agonists are currently in clinical trials for treatment of dislipidemia. If there is an effect on body weight in humans, it should become evident in these trials. Weight loss stimulated by PPARdelta synthetic ligand treatment is likely mediated by increased peripheral fatty acid oxidation, which also contributes to improvement in insulin sensitivity.

Due to its essential role in adipocyte differentiation and maintenance, PPARgamma antagonist are alluring anti-obesity drugs. However, if fatty acids are not stored in adipocytes, they will accumulate elsewhere. Increased plasma FFAs in addition to other mechanisms will most likely lead to insulin resistance upon PPARgamma inhibition. In addition to increasing insulin sensitivity, PPARgamma agonism has other desirable effects, such as suppression of inflammatory response and stimulation of LXR transcription in macrophages, both of which reduce the risk of developing atherosclerosis.26,143 Activation of LXR via synthetic ligand increases the expression of the cholesterol transporters ABCA1 and ABCG1, thereby increasing cholesterol efflux to HDL.29,142,150,176,177 In addition, LXR stimulates expression of apoE in the macrophage.92 The importance of apoE-mediated lipoprotein uptake is highlighted in the apoE knockout mouse which spontaneously develops atherosclerosis, even on normal chow.31 Reintroduction of apoE into only macrophages protects from atherosclerosis, indicating the importance of macrophage apoE expression.14,104

In addition to effects on cholesterol metabolism, LXR ligand stimulation reduces inflammation, further protecting from the development of foam cells.76 The VDR is also a potential target for reducing atherogenic inflammation. Activation of VDR has been shown to promote the development of lymphocytes into Th2 cells over Th1 cells.3,28,166 Since the cytokines released by Th1 cells are especially atherogenic, VDR activation may reduce atherogensis. Although the immunological effects of VDR are relatively weak, epidemiological evidence support the importance of vitamin D. Risk of coronary heart disease is decreased in southern Europe and at higher altitude in America, areas where sunlight exposure is higher.55,118,178 Vitamin A may also be an important nutrient due to the stimulation of RXR by the vitamin A metabolite 9-cis RA. Stimulation of many of the permissive class II subfamilies (PPAR, LXR and FXR) through RXR would have a beneficial effect on reducing the metabolic syndrome. Beta-carotene (BC) compounds naturally occurring in the 9-cis conformation are hydrolyzed to 9-cis RA and have been shown to increase the effectiveness of fibrates.152 In one study, 22 subjects on fibrates treatment were divided into a placebo and 9-cis BC treatment group.152 A statistically significant increase in HDL and decrease in TG in subjects receiving 9-cis BC relative to those receiving placebo was observed.152

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