Mechanistic Evaluation of PPARα-Mediated Hepatocarcinogenesis: Are We There Yet?

Open Access
Publisher Website
Google Scholar
Abstract
The fibrate class of hypolipidemic drugs have been used for many years as therapeutic agents to reduce serum triglycerides, increase serum high density lipoprotein cholesterol, and in doing so, improve the health of individuals with dyslipidemias. Long before the actual mechanism of action was delineated, it was postulated that these drugs functioned by activating a nuclear receptor. Indeed, the identification and cloning of the peroxisome proliferator–activated receptor-α (PPARα) (Issemann and Green, 1990) led to a plethora of research that definitively confirmed that PPARα was the central mediator for the hypolipidemic effects of fibrates. But the story actually became significantly more complicated over the years because it turned out that there were many other chemicals, collectively termed “peroxisome proliferators” that activated this receptor. More importantly, the seminal work by Reddy and colleagues showing that long-term administration of PPARα agonists caused liver cancer (Reddy et al., 1980) has raised serious concern regarding the safety of the collective class of compounds that activate PPARα, that humans are exposed to. There has been considerable research undertaken over the past 25 years examining the effect of peroxisome proliferators, including comparative analysis between a variety of species indicating that there is a species difference in the response to peroxisome proliferators (reviewed in Klaunig et al. [2003]; Peters et al. [2005]). The paper by (Yang et al. 2007) in this issue of Toxicological Sciences provides another turning point in this field.