PPARγ in Monocytes: Less Pain, Any Gain?

These papers represent intriguing data obtained from isolated monocytic cells. If the implications of the papers are realized in vivo, this may represent both good and bad news. Approximately 730,000 Americans now take a drug (troglitazone) known to function as a PPARγ ligand, so these are important issues. If a PPARγ ligand can effectively suppress monocytic activation, NO production, and the secretion of cytokines, this suggests that TZDs or other ligands could have a major impact on inflammatory disease. Since millions of people suffer from conditions of chronic inflammation, such as rheumatoid arthritis and inflammatory bowel disease, new orally active drugs to control inflammation would be welcomed. This is particularly true because high doses and prolonged application of NSAIDs are often difficult for patients to tolerate. Despite the recent announcement that troglitazone may cause a rare, idiosyncratic liver toxicity in some humans (Food and Drug Administration, 1997), most patients tolerate this drug with few, if any, side effects. To date, there have been no studies in animals or humans concerning the effects of a specific agonist for PPARγ on inflammation.The implications of the monocyte-foam cell papers are not so pleasant to contemplate. The TZD drugs are used to treat patients with noninsulin-dependent diabetes mellitus, a disease that carries a very large cardiovascular risk. When one considers that the vast majority of these patients in the U.S. and Europe are also obese, a condition that adds a second, independent cardiovascular risk, any acceleration of atherogenesis promoted by these drugs would clearly be unacceptable. What do the clinical data show to date? All of the antidiabetic TZD drugs lower blood lipids in both rodents and humans and, hence, would be expected to reduce cardiovascular risk. Preliminary data in humans taking troglitazone has shown, as expected, a reduction in atherosclerosis (Minamikawa et al. 1998xMinamikawa, J, Yamauchi, M, Inoue, D, and Koshiyama, H. J. Clinic. Endo. Met. 1998; 83: 1041CrossrefSee all ReferencesMinamikawa et al. 1998). There are several possible ways to reconcile these data. First, given that the monocyte to foam cell conversion shown in Tontonoz et al. 1998xTontonoz, P, Nagy, L, Alvarez, J.G.A, Thomazy, V.A, and Evans, R.M. Cell. 1998; 93: 241–252Abstract | Full Text | Full Text PDF | PubMed | Scopus (1353)See all ReferencesTontonoz et al. 1998 requires simultaneous application of PPARγ ligands and RXR agonists, the TZD drugs applied as a monotherapy may not achieve either the level of activation of PPARγ in vivo or activation of additional pathways (as discussed above) necessary for the foam cell reaction. Secondly, foam cell conversion is a highly visible component of atherosclerotic lesions but it is not clear that foam cell generation per se would necessarily promote clinically significant atherogenesis in the absence of other pathological processes occurring within blood vessels. Finally, it is conceivable that TZD activation of PPARγ may induce expression of scavenger receptors such as CD36 in other cells besides macrophages. This receptor is highly expressed in fat, for example, and its up-regulation by TZDs in this tissue could, in fact, provide a relatively benign sink for potentially deleterious oxLDL. This is an exciting possibility that should be investigated. The application of selective PPARγ agonists to animal models of inflammation and atherosclerosis should shed light on the ability of this receptor to modulate these important biological effects.