Reduced expression of peroxisome proliferator-activated receptor-α may have an important role in the development of non-alcoholic fatty liver disease

Jong Eun Yeon, Kyung Mook Choi, Sei-Hyun Baik, Oh Kim Kyoung, Joon Lim Hyoung, Ho Park Ki, Yong Kim Jin, Jong Jae Park, Jae Seon Kim, Young-Tae Bak, Kwan Soo Byun, Hong Lee Chang

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Abstract

Background: Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains poorly understood, metabolic syndrome associated with insulin resistance is the most reproducible factor in the development of NAFLD. Fat accumulation in hepatocytes results from an imbalance in the input, output and oxidation of fatty acid. Peroxisomes contain a battery of fatty acid oxidizing enzymes, the first of which, acyl-CoA oxidase (AOX), initiates the β-oxidation spiral. One of the mammalian peroxisome proliferator-activated receptors (PPAR), PPAR-α, regulates the transcriptional expression of the enzymes involved in fatty acid β-oxidation. The aim of the present study was to define the role of PPAR-α and AOX in the development of NAFLD using the Otsuka Long-Evans Tokushima fatty (OLETF) rat model. Methods: Liver tissue from OLETF (n = 12) and control (n = 10) rats 12, 28, and 40 weeks old were processed for histopathological and western blot analysis. The messenger RNA of PPAR-α and AOX were quantified by real-time RT-PCR. Results: At 40 weeks old, the histological analysis of the OLETF rat liver had steatosis (approximately 66%) and mild inflammation, which were comparable to those in NAFLD. Histological changes were unremarkable in 12 week and 28 week rats. In 12 week OLETF rats, the mRNA of AOX was 63% of the control. Expression of PPAR-α mRNA was also reduced to 3% that of the control. Along with the changes of mRNA, the protein expression of PPAR-α was also significantly reduced to 17% that of the control. In 28 week and 40 week animals, PPAR-α protein expression gradually increased to 75% and 78% that of the control. Expression of PPAR-α mRNA was also increased by up to 26% and 110% of the control. AOX, regulated by PPAR-α, also increased to 149% and 120% of the control. Conclusion: Reduced expression of PPAR-α and AOX was observed even before definite steatosis had developed. The alteration of peroxisomal fatty acid metabolism may have an important role in the development of NAFLD.

Original languageEnglish
Pages (from-to)799-804
Number of pages6
JournalJournal of Gastroenterology and Hepatology (Australia)
Volume19
Issue number7
DOIs
Publication statusPublished - 2004 Jan 1

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Peroxisome Proliferator-Activated Receptors
Acyl-CoA Oxidase
Inbred OLETF Rats
Fatty Acids
Messenger RNA
Fatty Liver
Non-alcoholic Fatty Liver Disease
Peroxisomes
Enzymes
Insulin Resistance
Real-Time Polymerase Chain Reaction
Hepatocytes
Proteins
Western Blotting
Fats
Inflammation

Keywords

  • Acyl-CoA oxidase
  • Beta oxidation
  • Fatty acid
  • Non-alcoholic fatty liver disease
  • Peroxisome proliferator-activated receptor-α

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology

Cite this

@article{11860b2b84484acfad537b2678615194,
title = "Reduced expression of peroxisome proliferator-activated receptor-α may have an important role in the development of non-alcoholic fatty liver disease",
abstract = "Background: Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains poorly understood, metabolic syndrome associated with insulin resistance is the most reproducible factor in the development of NAFLD. Fat accumulation in hepatocytes results from an imbalance in the input, output and oxidation of fatty acid. Peroxisomes contain a battery of fatty acid oxidizing enzymes, the first of which, acyl-CoA oxidase (AOX), initiates the β-oxidation spiral. One of the mammalian peroxisome proliferator-activated receptors (PPAR), PPAR-α, regulates the transcriptional expression of the enzymes involved in fatty acid β-oxidation. The aim of the present study was to define the role of PPAR-α and AOX in the development of NAFLD using the Otsuka Long-Evans Tokushima fatty (OLETF) rat model. Methods: Liver tissue from OLETF (n = 12) and control (n = 10) rats 12, 28, and 40 weeks old were processed for histopathological and western blot analysis. The messenger RNA of PPAR-α and AOX were quantified by real-time RT-PCR. Results: At 40 weeks old, the histological analysis of the OLETF rat liver had steatosis (approximately 66{\%}) and mild inflammation, which were comparable to those in NAFLD. Histological changes were unremarkable in 12 week and 28 week rats. In 12 week OLETF rats, the mRNA of AOX was 63{\%} of the control. Expression of PPAR-α mRNA was also reduced to 3{\%} that of the control. Along with the changes of mRNA, the protein expression of PPAR-α was also significantly reduced to 17{\%} that of the control. In 28 week and 40 week animals, PPAR-α protein expression gradually increased to 75{\%} and 78{\%} that of the control. Expression of PPAR-α mRNA was also increased by up to 26{\%} and 110{\%} of the control. AOX, regulated by PPAR-α, also increased to 149{\%} and 120{\%} of the control. Conclusion: Reduced expression of PPAR-α and AOX was observed even before definite steatosis had developed. The alteration of peroxisomal fatty acid metabolism may have an important role in the development of NAFLD.",
keywords = "Acyl-CoA oxidase, Beta oxidation, Fatty acid, Non-alcoholic fatty liver disease, Peroxisome proliferator-activated receptor-α",
author = "Yeon, {Jong Eun} and Choi, {Kyung Mook} and Sei-Hyun Baik and Kyoung, {Oh Kim} and Hyoung, {Joon Lim} and Ki, {Ho Park} and Jin, {Yong Kim} and Park, {Jong Jae} and Kim, {Jae Seon} and Young-Tae Bak and Byun, {Kwan Soo} and Chang, {Hong Lee}",
year = "2004",
month = "1",
day = "1",
doi = "10.1111/j.1440-1746.2004.03349.x",
language = "English",
volume = "19",
pages = "799--804",
journal = "Journal of Gastroenterology and Hepatology (Australia)",
issn = "0815-9319",
publisher = "Wiley-Blackwell",
number = "7",

}

TY - JOUR

T1 - Reduced expression of peroxisome proliferator-activated receptor-α may have an important role in the development of non-alcoholic fatty liver disease

AU - Yeon, Jong Eun

AU - Choi, Kyung Mook

AU - Baik, Sei-Hyun

AU - Kyoung, Oh Kim

AU - Hyoung, Joon Lim

AU - Ki, Ho Park

AU - Jin, Yong Kim

AU - Park, Jong Jae

AU - Kim, Jae Seon

AU - Bak, Young-Tae

AU - Byun, Kwan Soo

AU - Chang, Hong Lee

PY - 2004/1/1

Y1 - 2004/1/1

N2 - Background: Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains poorly understood, metabolic syndrome associated with insulin resistance is the most reproducible factor in the development of NAFLD. Fat accumulation in hepatocytes results from an imbalance in the input, output and oxidation of fatty acid. Peroxisomes contain a battery of fatty acid oxidizing enzymes, the first of which, acyl-CoA oxidase (AOX), initiates the β-oxidation spiral. One of the mammalian peroxisome proliferator-activated receptors (PPAR), PPAR-α, regulates the transcriptional expression of the enzymes involved in fatty acid β-oxidation. The aim of the present study was to define the role of PPAR-α and AOX in the development of NAFLD using the Otsuka Long-Evans Tokushima fatty (OLETF) rat model. Methods: Liver tissue from OLETF (n = 12) and control (n = 10) rats 12, 28, and 40 weeks old were processed for histopathological and western blot analysis. The messenger RNA of PPAR-α and AOX were quantified by real-time RT-PCR. Results: At 40 weeks old, the histological analysis of the OLETF rat liver had steatosis (approximately 66%) and mild inflammation, which were comparable to those in NAFLD. Histological changes were unremarkable in 12 week and 28 week rats. In 12 week OLETF rats, the mRNA of AOX was 63% of the control. Expression of PPAR-α mRNA was also reduced to 3% that of the control. Along with the changes of mRNA, the protein expression of PPAR-α was also significantly reduced to 17% that of the control. In 28 week and 40 week animals, PPAR-α protein expression gradually increased to 75% and 78% that of the control. Expression of PPAR-α mRNA was also increased by up to 26% and 110% of the control. AOX, regulated by PPAR-α, also increased to 149% and 120% of the control. Conclusion: Reduced expression of PPAR-α and AOX was observed even before definite steatosis had developed. The alteration of peroxisomal fatty acid metabolism may have an important role in the development of NAFLD.

AB - Background: Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains poorly understood, metabolic syndrome associated with insulin resistance is the most reproducible factor in the development of NAFLD. Fat accumulation in hepatocytes results from an imbalance in the input, output and oxidation of fatty acid. Peroxisomes contain a battery of fatty acid oxidizing enzymes, the first of which, acyl-CoA oxidase (AOX), initiates the β-oxidation spiral. One of the mammalian peroxisome proliferator-activated receptors (PPAR), PPAR-α, regulates the transcriptional expression of the enzymes involved in fatty acid β-oxidation. The aim of the present study was to define the role of PPAR-α and AOX in the development of NAFLD using the Otsuka Long-Evans Tokushima fatty (OLETF) rat model. Methods: Liver tissue from OLETF (n = 12) and control (n = 10) rats 12, 28, and 40 weeks old were processed for histopathological and western blot analysis. The messenger RNA of PPAR-α and AOX were quantified by real-time RT-PCR. Results: At 40 weeks old, the histological analysis of the OLETF rat liver had steatosis (approximately 66%) and mild inflammation, which were comparable to those in NAFLD. Histological changes were unremarkable in 12 week and 28 week rats. In 12 week OLETF rats, the mRNA of AOX was 63% of the control. Expression of PPAR-α mRNA was also reduced to 3% that of the control. Along with the changes of mRNA, the protein expression of PPAR-α was also significantly reduced to 17% that of the control. In 28 week and 40 week animals, PPAR-α protein expression gradually increased to 75% and 78% that of the control. Expression of PPAR-α mRNA was also increased by up to 26% and 110% of the control. AOX, regulated by PPAR-α, also increased to 149% and 120% of the control. Conclusion: Reduced expression of PPAR-α and AOX was observed even before definite steatosis had developed. The alteration of peroxisomal fatty acid metabolism may have an important role in the development of NAFLD.

KW - Acyl-CoA oxidase

KW - Beta oxidation

KW - Fatty acid

KW - Non-alcoholic fatty liver disease

KW - Peroxisome proliferator-activated receptor-α

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U2 - 10.1111/j.1440-1746.2004.03349.x

DO - 10.1111/j.1440-1746.2004.03349.x

M3 - Article

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EP - 804

JO - Journal of Gastroenterology and Hepatology (Australia)

JF - Journal of Gastroenterology and Hepatology (Australia)

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