Abstract
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.
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- ACOX1:
-
Acyl –CoA oxidase
- CAR:
-
Constitutive androstane receptor
- CRPC:
-
Castration-resistant prostate cancer
- CBP:
-
CREB binding protein
- CARM1:
-
Coactivator-associated arginine methyltransferase-1
- CRE:
-
cAMP response element
- CREB:
-
cAMP response element-binding
- DEHA:
-
Di-(2-ethylhexyl) adipate
- DEHP:
-
Di-(2-ethylhexyl)-phthalate
- DENA:
-
Diethylnitrosamine
- DRIP:
-
Vitamin D receptor-interacting protein(s)
- ER:
-
Endoplasmic reticulum
- GR:
-
Glucocorticoid receptor
- L-PBE:
-
L-bifunctional peroxisomal enzyme
- HAT:
-
Histone acetyl transferase
- MAPK:
-
Mitogen activated protein kinase
- Med1:
-
Mediator complex subunit 1
- MFP:
-
Multifunctional protein
- NCoA6IP:
-
Nuclear receptor coactivator 6 interacting protein
- PBP:
-
PPAR-binding protein
- PIMT:
-
PRIP interacting protein with methyltransferase domain
- PPAR:
-
Peroxisome proliferator-activated receptor
- PPRE:
-
Peroxisome proliferator response element
- PRIP:
-
PPAR-interacting protein
- RXR:
-
Retinoid-X-receptor
- SBP2:
-
Selenium binding protein-2
- SRC-1:
-
p160/steroid receptor coactivator-1
- VLCF:
-
Very long chain fatty acid
- Tibric Acid:
-
2-chloro-5-(3 5-dimethylpiperidinosulfonyl) benzoic acid
- Wy-14, 643:
-
[4-chloro-6-(2, 3-xylidino)-2-pyrimidinylthio] acetic acid
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Misra, P., Viswakarma, N., Reddy, J.K. (2013). Peroxisome Proliferator-Activated Receptor-α Signaling in Hepatocarcinogenesis. In: del Río, L. (eds) Peroxisomes and their Key Role in Cellular Signaling and Metabolism. Subcellular Biochemistry, vol 69. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6889-5_5
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