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Peroxisome Proliferator-Activated Receptor-α Signaling in Hepatocarcinogenesis

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Book cover Peroxisomes and their Key Role in Cellular Signaling and Metabolism

Part of the book series: Subcellular Biochemistry ((SCBI,volume 69))

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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Abbreviations

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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Authors and Affiliations

  1. Department of Biology, Dr. Reddy’s Institute of Life Sciences, An Associate Institute of University of Hyderabad, Gachibowli, Hyderabad, 500046, India

    Parimal Misra

  2. Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL, 60153, USA

    Navin Viswakarma

  3. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611-3008, USA

    Janardan K. Reddy

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  1. Parimal Misra
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  2. Navin Viswakarma
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  3. Janardan K. Reddy
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Correspondence to Parimal Misra .

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  1. , Depto. Bioquímica, Biología Celular y, Estación Experimental del Zaidín, CSIC, Profesor Albareda 1, Granada, 18008, Spain

    Luis A. del Río

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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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