Hepatocellular and hepatic peroxisomal alterations in mice with a disrupted peroxisomal fatty acyl-coenzyme A oxidase gene
Open accessAbstract
Peroxisomal genetic disorders, such as Zellweger syndrome, are characterized by defects in one or more enzymes involved in the peroxisomal beta-oxidation of very long chain fatty acids and are associated with defective peroxisomal biogenesis. The biologic role of peroxisomal beta-oxidation system, which consists of three enzymes: fatty acyl-CoA oxidase (ACOX), enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (HD), and thiolase, has been examined in mice by disrupting ACOX gene, which encodes the first and rate-limiting enzyme of this system. Homozygous (ACOX -/-) mice lacked the expression of ACOX protein and accumulate very long chain fatty acids in blood. However, these homozygous mice are viable, but growth-retarded and infertile. During the first 3-4 months of age, the livers of ACOX -/- mice reveal severe microvesicular fatty metamorphosis of hepatocytes. In such steatotic cells, peroxisome assembly is markedly defective; as a result, they contain few or no peroxisomes. Few hepatocytes in 1-3-month-old ACOX -/- mice contain numerous peroxisomes, and these peroxisome-rich hepatocytes show no fatty change. At this stage, the basal mRNA levels of HD, thiolase, and other peroxisome proliferator-induced target genes were elevated in ACOX -/- mouse liver, but these mice, when treated with a peroxisome proliferator, showed no increases in the number of hepatic peroxisomes and in the mRNAs levels of these target genes. Between 4 and 5 months of age, severe steatosis resulted in scattered cell death, steatohepatitis, formation of lipogranulomas, and focal hepatocellular regeneration. In 6-7-month-old animals, the newly emerging hepatocytes, which progressively replaced steatotic cells, revealed spontaneous peroxisome proliferation. These livers showed marked increases in the mRNA levels of the remaining two genes of the beta-oxidation system, suggesting that ACOX gene disruption leads to increased endogenous ligand-mediated transcription levels. These observations demonstrate links among peroxisomal beta-oxidation, development of severe microvesicular fatty liver, peroxisome assembly, cell death, and cell proliferation in liver.
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Acox1-KO mice accumulate VLCFAs in their brains but have neither axonal loss nor any neurodegenerative phenotype.
“Acox1-KO mice accumulate VLCFAs in their brains but have neither axonal loss [267] nor any neurodegenerative phenotype [268].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [267]
The Discussion reports no appreciable neurological manifestations in ACOX-null mice by six months of age. It does not establish that the mice lack any neurodegenerative phenotype at all ages; the authors explicitly leave open whether neurological dysfunction develops later. The separate axonal-loss clause is attached to citation [267], not this source. (LLM, conf=0.88)
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Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
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- Authors
- Fan, C.-Y., Pan, J., Chu, R., Lee, D., Kluckman, K. D., Usuda, N., Singh, I., Yeldandi, A. V., Rao, M. S., Maeda, N., & Reddy, J. K.
- Affiliations
- Northwestern University (US)
- University of North Carolina at Chapel Hill (US)
- Medical University of South Carolina (US)
- Corresponding author
- Reddy, Janardan K.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1996-10
- Volume
- 271
- Issue
- 40
- Pages
- 24698-24710
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2123116985
- Cited by
- 268
- References
- 1
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 14 · 2023: 7 · 2022: 9 · 2021: 9 · 2020: 12 · 2019: 10 · 2018: 10 · 2017: 5 · 2016: 2 · 2015: 9 · 2014: 11 · 2013: 10 · 2012: 11
- FWCI
- 4.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (GM23750)
- National Heart, Lung, and Blood Institute (HL 42630)
- National Institute of General Medical Sciences (R 37 GM23750, R37GM023750)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- acyl-CoA oxidase, peroxisomal beta-oxidation, very long chain fatty acids, Zellweger syndrome, peroxisome biogenesis, hepatocyte steatosis, enoyl-CoA hydratase, thiolase, hepatocyte death, hepatocyte proliferation, lipogranuloma
- MeSH terms
- Animals, Cell Line, Fatty Liver, Female, Fetal Growth Retardation, Homozygote, Liver, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Mutant Strains, Microbodies, Microscopy, Electron, Microsomes, Liver, Oxidoreductases, Phenotype, Pregnancy, RNA, Messenger, Up-Regulation, Acyl-CoA Oxidase, Lipid Metabolism, Mice
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