The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Liver insufficiency and damage are major causes of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals, and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPAR beta/delta(-/-) mouse is more susceptible to chemically induced hepatotoxicity than its wild-type counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPAR beta/delta confers protection to hepatocytes. We hypothesized that PPAR beta/delta plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadecadienoic acid (13-S-HODE) and 441NE are PPAR beta/delta ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPAR beta/delta subtype while 4-hyroxyhexenal (4-HRE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPAR beta/delta activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPAR beta/delta-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPAR beta/delta activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage. (c) 2007 Elsevier Inc. All rights reserved.