Peroxisomal and mitochondrial fatty acid β-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor and peroxisomal fatty acyl-CoA oxidase: Genotype correlation with fatty liver phenotype

Takashi Hashimoto, Tomoyuki Fujita, Nobuteru Usuda, William Cook, Chao Qi, Jeffrey M. Peters, Frank J. Gonzalez, Anjana V. Yeldandi, M. Sambasiva Rao, Janardan K. Reddy

Research output: Contribution to journalArticle

202 Citations (Scopus)

Abstract

Fatty acid β-oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also metabolized by the cytochrome P450 CYP4A ω- oxidation enzymes to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal β-oxidation. Synthetic peroxisome proliferators interact with peroxisome proliferator activated receptor α (PPARα) to transcriptionally activate genes that participate in peroxisomal, microsomal, and mitochondrial fatty acid oxidation. Mice lacking PPARα (PPARα(-/-)) fail to respond to the inductive effects of peroxisome proliferators, whereas those lacking fatty acyl-CoA oxidase (AOX(-/-)), the first enzyme of the peroxisomal β-oxidation system, exhibit extensive microvesicular steatohepatitis, leading to hepatocellular regeneration and massive peroxisome proliferation, implying sustained activation of PPARα by natural ligands. We now report that mice nullizygous for both PPARα and AOX (PPARα(-/-) AOX(-/-)) failed to exhibit spontaneous peroxisome proliferation and induction of PPARα-regulated genes by biological ligands unmetabolized in the absence of AOX. In AOX(-/-) mice, the hyperactivity of PPARα enhances the severity of steatosis by inducing CYP4A family proteins that generate DCAs and since they are not metabolized in the absence of peroxisomal β- oxidation, they damage mitochondria leading to steatosis. Blunting of microvesicular steatosis, which is restricted to few liver cells in periportal regions in PPARα(-/-) AOX(-/-) mice, suggests a role for PPARα- induced genes, especially members of CYP4A family, in determining the severity of steatosis in livers with defective peroxisomal β-oxidation. In age-matched PPARα(-/-) mice, a decrease in constitutive mitochondrial β- oxidation with intact constitutive peroxisomal β-oxidation system contributes to large droplet fatty change that is restricted to centrilobular hepatocytes. These data define a critical role for both PPARα and AOX in hepatic lipid metabolism and in the pathogenesis of specific fatty liver phenotype.

Original languageEnglish (US)
Pages (from-to)19228-19236
Number of pages9
JournalJournal of Biological Chemistry
Volume274
Issue number27
DOIs
StatePublished - Jul 2 1999

Fingerprint

Acyl-CoA Oxidase
Peroxisome Proliferator-Activated Receptors
Fatty Liver
Liver
Fatty Acids
Genotype
Phenotype
Oxidation
Cytochrome P-450 CYP4A
Peroxisomes
Peroxisome Proliferators
Dicarboxylic Acids
Mitochondria
Genes
peroxisomal acyl-CoA oxidase
Ligands
Poisons
Enzymes
Lipid Metabolism
Cytochrome P-450 Enzyme System

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Hashimoto, Takashi ; Fujita, Tomoyuki ; Usuda, Nobuteru ; Cook, William ; Qi, Chao ; Peters, Jeffrey M. ; Gonzalez, Frank J. ; Yeldandi, Anjana V. ; Rao, M. Sambasiva ; Reddy, Janardan K. / Peroxisomal and mitochondrial fatty acid β-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor and peroxisomal fatty acyl-CoA oxidase : Genotype correlation with fatty liver phenotype. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 27. pp. 19228-19236.
@article{2ecde6cdb4a74fdeb190883f5fa6c90c,
title = "Peroxisomal and mitochondrial fatty acid β-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor and peroxisomal fatty acyl-CoA oxidase: Genotype correlation with fatty liver phenotype",
abstract = "Fatty acid β-oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also metabolized by the cytochrome P450 CYP4A ω- oxidation enzymes to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal β-oxidation. Synthetic peroxisome proliferators interact with peroxisome proliferator activated receptor α (PPARα) to transcriptionally activate genes that participate in peroxisomal, microsomal, and mitochondrial fatty acid oxidation. Mice lacking PPARα (PPARα(-/-)) fail to respond to the inductive effects of peroxisome proliferators, whereas those lacking fatty acyl-CoA oxidase (AOX(-/-)), the first enzyme of the peroxisomal β-oxidation system, exhibit extensive microvesicular steatohepatitis, leading to hepatocellular regeneration and massive peroxisome proliferation, implying sustained activation of PPARα by natural ligands. We now report that mice nullizygous for both PPARα and AOX (PPARα(-/-) AOX(-/-)) failed to exhibit spontaneous peroxisome proliferation and induction of PPARα-regulated genes by biological ligands unmetabolized in the absence of AOX. In AOX(-/-) mice, the hyperactivity of PPARα enhances the severity of steatosis by inducing CYP4A family proteins that generate DCAs and since they are not metabolized in the absence of peroxisomal β- oxidation, they damage mitochondria leading to steatosis. Blunting of microvesicular steatosis, which is restricted to few liver cells in periportal regions in PPARα(-/-) AOX(-/-) mice, suggests a role for PPARα- induced genes, especially members of CYP4A family, in determining the severity of steatosis in livers with defective peroxisomal β-oxidation. In age-matched PPARα(-/-) mice, a decrease in constitutive mitochondrial β- oxidation with intact constitutive peroxisomal β-oxidation system contributes to large droplet fatty change that is restricted to centrilobular hepatocytes. These data define a critical role for both PPARα and AOX in hepatic lipid metabolism and in the pathogenesis of specific fatty liver phenotype.",
author = "Takashi Hashimoto and Tomoyuki Fujita and Nobuteru Usuda and William Cook and Chao Qi and Peters, {Jeffrey M.} and Gonzalez, {Frank J.} and Yeldandi, {Anjana V.} and Rao, {M. Sambasiva} and Reddy, {Janardan K.}",
year = "1999",
month = "7",
day = "2",
doi = "10.1074/jbc.274.27.19228",
language = "English (US)",
volume = "274",
pages = "19228--19236",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "27",

}

Peroxisomal and mitochondrial fatty acid β-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor and peroxisomal fatty acyl-CoA oxidase : Genotype correlation with fatty liver phenotype. / Hashimoto, Takashi; Fujita, Tomoyuki; Usuda, Nobuteru; Cook, William; Qi, Chao; Peters, Jeffrey M.; Gonzalez, Frank J.; Yeldandi, Anjana V.; Rao, M. Sambasiva; Reddy, Janardan K.

In: Journal of Biological Chemistry, Vol. 274, No. 27, 02.07.1999, p. 19228-19236.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Peroxisomal and mitochondrial fatty acid β-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor and peroxisomal fatty acyl-CoA oxidase

T2 - Genotype correlation with fatty liver phenotype

AU - Hashimoto, Takashi

AU - Fujita, Tomoyuki

AU - Usuda, Nobuteru

AU - Cook, William

AU - Qi, Chao

AU - Peters, Jeffrey M.

AU - Gonzalez, Frank J.

AU - Yeldandi, Anjana V.

AU - Rao, M. Sambasiva

AU - Reddy, Janardan K.

PY - 1999/7/2

Y1 - 1999/7/2

N2 - Fatty acid β-oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also metabolized by the cytochrome P450 CYP4A ω- oxidation enzymes to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal β-oxidation. Synthetic peroxisome proliferators interact with peroxisome proliferator activated receptor α (PPARα) to transcriptionally activate genes that participate in peroxisomal, microsomal, and mitochondrial fatty acid oxidation. Mice lacking PPARα (PPARα(-/-)) fail to respond to the inductive effects of peroxisome proliferators, whereas those lacking fatty acyl-CoA oxidase (AOX(-/-)), the first enzyme of the peroxisomal β-oxidation system, exhibit extensive microvesicular steatohepatitis, leading to hepatocellular regeneration and massive peroxisome proliferation, implying sustained activation of PPARα by natural ligands. We now report that mice nullizygous for both PPARα and AOX (PPARα(-/-) AOX(-/-)) failed to exhibit spontaneous peroxisome proliferation and induction of PPARα-regulated genes by biological ligands unmetabolized in the absence of AOX. In AOX(-/-) mice, the hyperactivity of PPARα enhances the severity of steatosis by inducing CYP4A family proteins that generate DCAs and since they are not metabolized in the absence of peroxisomal β- oxidation, they damage mitochondria leading to steatosis. Blunting of microvesicular steatosis, which is restricted to few liver cells in periportal regions in PPARα(-/-) AOX(-/-) mice, suggests a role for PPARα- induced genes, especially members of CYP4A family, in determining the severity of steatosis in livers with defective peroxisomal β-oxidation. In age-matched PPARα(-/-) mice, a decrease in constitutive mitochondrial β- oxidation with intact constitutive peroxisomal β-oxidation system contributes to large droplet fatty change that is restricted to centrilobular hepatocytes. These data define a critical role for both PPARα and AOX in hepatic lipid metabolism and in the pathogenesis of specific fatty liver phenotype.

AB - Fatty acid β-oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also metabolized by the cytochrome P450 CYP4A ω- oxidation enzymes to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal β-oxidation. Synthetic peroxisome proliferators interact with peroxisome proliferator activated receptor α (PPARα) to transcriptionally activate genes that participate in peroxisomal, microsomal, and mitochondrial fatty acid oxidation. Mice lacking PPARα (PPARα(-/-)) fail to respond to the inductive effects of peroxisome proliferators, whereas those lacking fatty acyl-CoA oxidase (AOX(-/-)), the first enzyme of the peroxisomal β-oxidation system, exhibit extensive microvesicular steatohepatitis, leading to hepatocellular regeneration and massive peroxisome proliferation, implying sustained activation of PPARα by natural ligands. We now report that mice nullizygous for both PPARα and AOX (PPARα(-/-) AOX(-/-)) failed to exhibit spontaneous peroxisome proliferation and induction of PPARα-regulated genes by biological ligands unmetabolized in the absence of AOX. In AOX(-/-) mice, the hyperactivity of PPARα enhances the severity of steatosis by inducing CYP4A family proteins that generate DCAs and since they are not metabolized in the absence of peroxisomal β- oxidation, they damage mitochondria leading to steatosis. Blunting of microvesicular steatosis, which is restricted to few liver cells in periportal regions in PPARα(-/-) AOX(-/-) mice, suggests a role for PPARα- induced genes, especially members of CYP4A family, in determining the severity of steatosis in livers with defective peroxisomal β-oxidation. In age-matched PPARα(-/-) mice, a decrease in constitutive mitochondrial β- oxidation with intact constitutive peroxisomal β-oxidation system contributes to large droplet fatty change that is restricted to centrilobular hepatocytes. These data define a critical role for both PPARα and AOX in hepatic lipid metabolism and in the pathogenesis of specific fatty liver phenotype.

UR - http://www.scopus.com/inward/record.url?scp=0033516569&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033516569&partnerID=8YFLogxK

U2 - 10.1074/jbc.274.27.19228

DO - 10.1074/jbc.274.27.19228

M3 - Article

C2 - 10383430

AN - SCOPUS:0033516569

VL - 274

SP - 19228

EP - 19236

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 27

ER -