The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta).
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 PPARbeta/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 PPARbeta/delta confers protection to hepatocytes. We hypothesized that PPARbeta/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 4-HNE are PPARbeta/delta ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARbeta/delta subtype while 4-hyroxyhexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPARbeta/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 PPARbeta/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 PPARbeta/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.
Coleman
Jeffrey D
JD
Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, 325 Life Sciences Building, The Pennsylvania State University, University Park, PA 16802, USA.
Prabhu
K Sandeep
KS
Thompson
Jerry T
JT
Reddy
P Sreenivasula
PS
Peters
Jeffrey M
JM
Peterson
Blake R
BR
Reddy
C Channa
CC
Vanden Heuvel
John P
JP
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000502:physiology; D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D008041:Linoleic Acids / Q000097:blood / Q000737:chemistry; D008079:Lipoproteins, VLDL / Q000097:blood; D051379:Mice; D008958:Models, Molecular; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D047495:PPAR gamma / Q000737:chemistry / Q000235:genetics*; D048068:PPAR-beta / Q000737:chemistry / Q000235:genetics*; D010957:Plasmids; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic
D000447:Aldehydes; D008041:Linoleic Acids; D008079:Lipoproteins, VLDL; D047495:PPAR gamma; D048068:PPAR-beta; D012333:RNA, Messenger; C024348:13-hydroxy-9,11-octadecadienoic acid; C027576:4-hydroxy-2-nonenal