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Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis.
Curr Mol Med. 2003 Sep; 3(6):561-72.CM

Abstract

Fatty acids are metabolized in the liver by beta-oxidation in mitochondria and peroxisomes and by omega-oxidation in microsomes. Peroxisomal beta-oxidation is responsible for the metabolism of very long chain fatty acids and mitochondrial beta-oxidation is responsible for the oxidation of short, medium and long chain fatty acids. Very long chain fatty acids are also metabolized by the cytochrome P450 CYP4A omega-oxidation system to dicarboxylic acids. Both peroxisomal beta-oxidation and microsomal omega-oxidation lead to the generation of H2O2. The genes encoding peroxisomal, microsomal and some mitochondrial fatty acid metabolizing enzymes in the liver are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha). Sustained activation of PPAR alpha by peroxisome proliferators has been shown to induce hepatocellular carcinomas in rats and mice. The peroxisome proliferator-induced carcinogenic effect has been attributed to transcriptional activation of PPAR alpha regulated genes and the resulting excessive generation of H2O2. Evidence from mice lacking fatty acyl-CoA oxidase (AOX), PPAR alpha and PPAR alpha/AOX has confirmed the role of PPAR alpha in the development of hepatocellular carcinomas. In addition, mice lacking AOX developed steatohepatitis and provided clues regarding the molecular mechanism responsible for steatosis and steatohepatitis and the role of unmetabolized AOX substrates in the activation of PPAR alpha.

Authors+Show Affiliations

Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

14527087

Citation

Yu, Songtao, et al. "Peroxisome Proliferator-activated Receptors, Fatty Acid Oxidation, Steatohepatitis and Hepatocarcinogenesis." Current Molecular Medicine, vol. 3, no. 6, 2003, pp. 561-72.
Yu S, Rao S, Reddy JK. Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis. Curr Mol Med. 2003;3(6):561-72.
Yu, S., Rao, S., & Reddy, J. K. (2003). Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis. Current Molecular Medicine, 3(6), 561-72.
Yu S, Rao S, Reddy JK. Peroxisome Proliferator-activated Receptors, Fatty Acid Oxidation, Steatohepatitis and Hepatocarcinogenesis. Curr Mol Med. 2003;3(6):561-72. PubMed PMID: 14527087.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis. AU - Yu,Songtao, AU - Rao,Sambasiva, AU - Reddy,Janardan K, PY - 2003/10/7/pubmed PY - 2003/12/5/medline PY - 2003/10/7/entrez SP - 561 EP - 72 JF - Current molecular medicine JO - Curr Mol Med VL - 3 IS - 6 N2 - Fatty acids are metabolized in the liver by beta-oxidation in mitochondria and peroxisomes and by omega-oxidation in microsomes. Peroxisomal beta-oxidation is responsible for the metabolism of very long chain fatty acids and mitochondrial beta-oxidation is responsible for the oxidation of short, medium and long chain fatty acids. Very long chain fatty acids are also metabolized by the cytochrome P450 CYP4A omega-oxidation system to dicarboxylic acids. Both peroxisomal beta-oxidation and microsomal omega-oxidation lead to the generation of H2O2. The genes encoding peroxisomal, microsomal and some mitochondrial fatty acid metabolizing enzymes in the liver are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha). Sustained activation of PPAR alpha by peroxisome proliferators has been shown to induce hepatocellular carcinomas in rats and mice. The peroxisome proliferator-induced carcinogenic effect has been attributed to transcriptional activation of PPAR alpha regulated genes and the resulting excessive generation of H2O2. Evidence from mice lacking fatty acyl-CoA oxidase (AOX), PPAR alpha and PPAR alpha/AOX has confirmed the role of PPAR alpha in the development of hepatocellular carcinomas. In addition, mice lacking AOX developed steatohepatitis and provided clues regarding the molecular mechanism responsible for steatosis and steatohepatitis and the role of unmetabolized AOX substrates in the activation of PPAR alpha. SN - 1566-5240 UR - https://www.unboundmedicine.com/medline/citation/14527087/Peroxisome_proliferator_activated_receptors_fatty_acid_oxidation_steatohepatitis_and_hepatocarcinogenesis_ L2 - https://www.ingentaconnect.com/openurl?genre=article&issn=1566-5240&volume=3&issue=6&spage=561&aulast=Yu DB - PRIME DP - Unbound Medicine ER -