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And PPAR Agonists: Is Rational Multitargeted Polypharmacy the Future of Therapeutics in Complex Diseases?
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
SUMMARY
The development of atherosclerosis can, in the absence of intervention, lead to cardiovascular disease, which is responsible for the demise of more Americans per year than any other disease. Beyer and colleagues report, in the Journal of Pharmacology and Experimental Therapeutics, that treating mice with a liver X receptor (LXR) agonist increases not only the concentration of circulating high-density lipoprotein (HDL) but also, unfortunately, that of circulating triglycerides. When doubly treated with LXR agonists together with peroxisome proliferator–activated receptor 
(PPAR) agonists, mice exhibited reduced concentrations of circulating triglycerides (but interestingly, triglyceride concentrations in the liver were not reduced) while their HDL concentrations remained elevated. The authors suggest that activation of both receptors, through the development and use of LXR–PPAR dual agonists, might become a useful therapy to bolster HDL levels while simultaneously suppressing circulating triglycerides in patients.
Pathologic changes caused by atherosclerosis in the cardiovascular system, such as coronary heart disease, aneuyrisms of the aorta, and ischemia/infarction of the brain or limbs, are nowadays the most profound threat to the quality and expectancy of life in developed countries (1). Lipid metabolism and circulating cholesterol and triglycerides are crucial in the development of atherosclerosis. Native low-density lipoprotein (LDL) is manufactured and secreted into the circulation by the liver as a carrier of cholesterol to peripheral tissues. Macrophages contribute to the vascular accumulation of cholesterol by absorbing the oxidized forms of LDL and adhering to inflamed endothelium to ultimately form stenosis-causing plaques (2). Pharmacologic interventions that reduce the serum levels of LDL cholesterol by inhibiting de novo synthesis of cholesterol from AcetylCoA in the liver, such as the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors termed statins, together with dietary restriction of cholesterol uptake, are the main preventive/therapeutic approach to atherosclerosis-related pathologic conditions (3).
Macrophages are capable of excreting cholesterol into the circulation as high-density lipoprotein (HDL), in combination with the apolipoprotein (apo) A1 and E1 acceptor molecules. Circulating HDL is then taken up by the liver and its cholesterol fraction is directly excreted into the bile or metabolized to bile acids (4, 5). The reverse cholesterol movement from the periphery to the liver is a promising novel target for pharmacologic intervention in the prevention or treatment of atherosclerosis. Agonists of the liver X receptor (LXR) influence this pathway and produce beneficial effects on lipid metabolism, indicating that they can be used against atherosclerosis (6–8). LXR, which functions as a sensor of cholesterol levels in tissues (5–8), is a type II nuclear receptor that consists of two isoforms, LXR and LXRß. The former is important for the regulation of cholesterol metabolism, and is expressed in the liver, spleen, adipose tissue, lung, and pituitary gland, whereas the latter is expressed ubiquitously. LXR binds to and is activated by a variety of oxysterols, such as 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, 24(S), 25-epoxycholesterol, and 27-hydroxycholesterol, as well as by metabolites of the mevalonate cholesterol synthesis pathway.
Activated LXR stimulates transcription by forming a heterodimer with the retinoid X receptor (RXR) and binding to the consensus responsive sequence DR4 in the promoter regions of several target genes, including those of cholesterol 7-hydroxylase (CYP7A1), cholesterol ester–transfer protein (CETP), ATP-binding cassette proteins (ABC), apolipoprotein E (ApoE), lipoprotein lipase (LPL), and sterol response element-binding protein 1c (SREBP-1c). Through transcriptional regulation of these and other target molecules, LXR decreases circulating LDL and tissue cholesterol by 1) facilitating cholesterol excretion in the gallbladder and catabolism through bile acid formation in the liver, 2) reducing cholesterol absorption in the intestine, and 3) promoting cholesterol efflux from peripheral tissues such as resident macrophages (Figure 1
) (6–8). LXR agonists also increase circulating levels of HDL cholesterol by stimulating the expression of ABCA1, apoE, and phospholipid transfer protein (PLTP) (9).
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agonists in addition to conventional cholesterol-lowering compounds could produce added benefit in the treatment/ prevention of atherosclerosis.
The apparent beneficial effects of LXR agonists on lipid metabolism, including a decrease of LDL and an increase of HDL, however, are associated with increased lipogenesis and production of triglycerides in the liver with resultant hypertriglyceridemia, an independent risk factor for atherosclerosis (Figure 1
) (8, 10). This activity of LXR is mediated by its induction of SREBP-1c, fatty acid synthase (FAS), sterol coenzyme A desaturase 1 (SCD-1), and acyl coenzyme A carboxylase (ACC) via direct activation of their promoters (8). SREBP-1c, a helix-loop-helix type transcription factor, plays a central role in LXR-mediated lipogenesis by stimulating the transcription rates of several genes whose products are associated with fatty acid metabolism (10). Development of selective LXR agonists, preserving the beneficial reverse cholesterol transport effect but devoid of the triglyceride-producing effect, would be ideal for the prevention or treatment of atherosclerosis, but no such compounds are as yet available.
In their recent article in The Journal of Pharmacology and Experimental Therapeutics, Beyer et al. attempted to diminish the pro-lipogenesis and hypertriglyceridemia effect of LXR agonists by co-administering peroxisome proliferator activator receptor (PPAR) agonists, known anti-lipogenic compounds (11, 12). Like the LXRs, PPAR belongs to the nuclear receptor superfamily and is distributed in tissues that have high lipid-metabolizing activity, such as the liver, brown fat, kidney, heart and skeletal muscles. Fatty acids, eicosanoids, and the fibrates (e.g., fenofibrate, clofibrate, and WY14643), a well-known class of hypolipidemic drugs,s are PPAR ligands (5). As with the LXRs, PPAR forms a heterodimer with RXR and stimulates the transcriptional activity of its responsive genes by binding to its consensus sequence, DR1, located in their promoter regions. PPAR activates ß-oxidation in the liver, generating energy by catabolizing fatty acids, by increasing the transcription rates of the genes of several enzymes involved in this process. Furthermore, PPAR increases the production of the apolipoproteins apoAV and apoCIII, which results in decreased levels of triglycerides in the circulation (12). Thus, activation of PPAR reduces the fatty acid content of the liver and the circulating levels of triglycerides––exactly the reverse of the effects of LXR activation (Figure 1). Some of the PPAR agonists also slightly increase HDL cholesterol in humans (13), thus working in the same direction with the LXR agonists.
Bayer et al. demonstrated that co-treatment of mice with the LXR agonist T0901317 and the PPAR agonists fenofibrate or WY14643 successfully attenuated the elevation of circulating triglycerides induced by LXR activation, even though the content of triglycerides in the liver persisted at elevated levels (11). The expression of SREBP-1c remained stimulated during the co-administration of the LXR and PPAR agonists, whereas fatty acid ß-oxidation in the liver was increased, explaining the observed triglyceride findings in the serum and liver. The combined treatment also produced synergistic elevation of the serum levels of HDL-cholesterol, enlargement in the diameter of the HDL particles, and an increase of their apoE and apoAI but not apoB content. A synergistic increase of liver PLTP might have contributed to the enlargement of the HDL particles. These results indicate that co-administration of PPAR agonists may be helpful in eliminating or reducing a significant unwanted effect of LXR agonists, hypertriglyceridemia, while it might enhance their beneficial effects on the vasculature by increasing HDL-cholesterol and enlarging the HDL particles. And, importantly, this combined treatment exerts these effects while allowing the increased cholesterol efflux and excretion caused by LXR agonists. Thus, pharmacologic manipulation of LXR agonism by PPAR ligands may provide a novel way to exploit the ability of LXR ligands to prevent/treat dyslipidemia and atherosclerosis.
There are additional complexities in the combined actions of LXR and PPAR systems (Figure 2). First, activation of PPAR induces the expression of the LXR gene through PPAR response elements located in the promoter of this gene in both hepatocytes and adipocytes (14, 15). Second, some fatty acids and the acidic forms of fibrates both bind LXR and suppress its transcriptional activity, and function as ligand agonists of PPAR (16–18). Third, LXR and PPAR may suppress each other’s transcriptional activity by competing for possibly limited amounts of their common heterodimer partner RXR (19, 20). Fourth, LXR increases its own protein expression through direct activation of its promoter (21). These remarkable complexities in the interaction between the LXR and PPAR signaling pathways and their target effects might produce unexpected biological actions in humans and other species, especially when LXR and PPAR agonists are simultaneously administered for the long-term. We know very little about the carcinogenic potential of LXR agonists, whereas PPAR agonists can act as carcinogenic agents in the rodent liver, possibly through stimulation of H2O2 generation during the ß-oxidation of fatty acids (1, 22). Thus, extensive bench, animal, and clinical research is necessary before rational, combined therapeutic regimens using LXR and PPAR agonists reach wide clinical practice.
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References
through PPAR response elements located in the promoter of the LXR gene.) versus liver X receptor. J. Biol. Chem. 278, 2403–2410 (2003). This paper was the first to describe the regulation of LXR transcriptional activity by acidic forms of fibrates. and PPAR for their heterodimer partner RXR.This article has been cited by other articles:
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  H.-S. Hoe, M. J. Cooper, M. P. Burns, P. A. Lewis, M. van der Brug, G. Chakraborty, C. M. Cartagena, D. T. S. Pak, M. R. Cookson, and G. W. Rebeck The Metalloprotease Inhibitor TIMP-3 Regulates Amyloid Precursor Protein and Apolipoprotein E Receptor Proteolysis J. Neurosci., October 3, 2007; 27(40): 10895 - 10905. [Abstract] [Full Text] [PDF]
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