Peroxisomes are subcellular organelles that are found in the cytoplasm of most animal cells. They perform diverse metabolic functions, including H2O2-derived respiration, β-oxidation of
fatty acids, and
cholesterol metabolism.
Peroxisome proliferators are a large class of structurally dissimilar industrial and
pharmaceutical chemicals that were originally identified as inducers of both the size and the number of peroxisomes in rat and mouse livers or hepatocytes in vitro. Exposure to
peroxisome proliferators leads to a stereotypical orchestration of adaptations consisting of hepatocellular
hypertrophy and
hyperplasia, and transcriptional induction of
fatty acid metabolizing
enzymes regulated in parallel with peroxisome proliferation. Chronic exposure to
peroxisome proliferators causes liver
tumors in both male and female mice and rats. Evidence indicates a pivotal role for a subset of
nuclear receptor superfamily members, called
peroxisome proliferator-activated receptors (PPARs), in mediating energy metabolism. Upon activation, PPARs regulate the expression of genes involved in lipid metabolism and peroxisome proliferation, as well as genes involved in cell growth. In this review, we describe the molecular mode of action of
PPAR transcription factors, including
ligand binding, interaction with specific
DNA response elements, transcriptional activation, and cross talk with other signaling pathways. We discuss the evidence that suggests that PPARα and transcriptional coactivator Med1/PBP, a key subunit of the
Mediator complex play a central role in mediating hepatic steatosis to hepatocarcinogenesis. Disproportionate increases in H2O2-generating
enzymes generates excess
reactive oxygen species resulting in sustained oxidative stress and progressive endoplasmic reticulum (ER) stress with activation of unfolded protein response signaling. Thus, these major contributors coupled with hepatocellular proliferation are the key players of
peroxisome proliferators-induced hepatocarcinogenesis.