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Cited by 476Liver Disease Diagnosis and TreatmentPeroxisome Proliferator-Activated ReceptorsDrug-Induced Hepatotoxicity and Protection

Central Role of Pparα–Dependent Hepatic Lipid Turnover in Dietary Steatohepatitis in Mice

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Ip, Emilia, Farrell, Geoffrey C., Robertson, Graham, Hall, Pauline, Kirsch, Richard, Leclercq, Isabelle·2003·Hepatology
DOI 10.1053/jhep.2003.50307
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Abstract

We have proposed that steatohepatitis results from reactive oxygen species (ROS) acting on accumulated fatty acids to form proinflammatory lipoperoxides. Cytochrome P450 4a (Cyp4a) and Cyp2e1 are potential hepatic sources of ROS. We tested the hypothesis that increasing Cyp4a through activation of peroxisome proliferator–activated receptor α (PPARα) should aggravate steatohepatitis produced by feeding a methionine and choline deficient (MCD) diet. Conversely, we assessed dietary steatohepatitis in PPARα -/- mice that cannot up–regulate Cyp4a. Male wild type (wt) or PPARα -/- mice (C57BL6 background) were fed the MCD diet with or without Wy–14,643 (0.1% wt/wt), a potent PPARα agonist. Controls were fed the same diet supplemented with methionine and choline. After 5 weeks, wt mice fed the MCD diet developed moderate steatohepatitis and alanine aminotransferase (ALT) levels were increased. Wy–14,643 prevented rather than increased liver injury; ALT levels were only mildly elevated whereas steatohepatitis was absent. Wy–14,643 up–regulated mRNA for liver fatty acid binding protein and peroxisomal β–oxidation enzymes (acyl–CoA oxidase, bifunctional enzyme, and ketothiolase), thereby reducing hepatic triglycerides and preventing steatosis. In wt mice, dietary feeding up–regulated Cyp4a14 mRNA 2.7–fold and increased hepatic lipoperoxides compared with controls. Wy–14,643 prevented hepatic lipoperoxides from accumulating despite an 18–fold increase in both Cyp4a10 and Cyp4a14 mRNA. PPARα -/- mice fed the MCD diet developed more severe steatohepatitis than wt mice, and were unaffected by Wy–14,643. In conclusion, PPARα activation both increases Cyp4a expression and enhances hepatic lipid turnover; the latter effect removes fatty acids as substrate for lipid peroxidation and is sufficiently powerful to prevent the development of dietary steatohepatitis.

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  • Pro-inflammatory responses negatively regulate PPARα in rodent models of atherosclerosis and early NAFLD, which could be affecting astronauts as well.

    “Pro-inflammatory responses negatively regulate PPARα in rodent models of atherosclerosis and early NAFLD that could be affecting astronauts as well75,76,79,80.”

    From Key points for the development of antioxidant cocktails to prevent cellular stress and damage caused by reactive oxygen species (ROS) during manned space missions (2021) · cites this paper as [80]

    The Discussion reports reduced expression of PPARα-regulated genes in mice fed a steatohepatitis-inducing diet, so it supports a related observation in a rodent liver-disease model. It does not show that pro-inflammatory responses negatively regulate PPARα itself, or address rodent atherosclerosis or effects in astronauts. The Discussion instead describes PPARα activation as potentially repressing inflammatory signaling; page numbers were not available in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • PPARα-null mice exhibit severe fatty liver and steatohepatitis, and patients with NASH show reduced expression of liver PPARα.

    “PPARα-null mice exhibit phenotypes such as severe fatty liver and steatohepatitis [101] and patients with NASH show a reduced expression of liver PPARα [102].”

    From Pemafibrate, a new selective PPARα modulator: drug concept and its clinical applications for dyslipidemia and metabolic diseases (2020) · cites this paper as [101]

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Authors
Ip, E., Farrell, G. C., Robertson, G., Hall, P., Kirsch, R., & Leclercq, I.
Affiliations
  • The University of Sydney (AU)
  • University of Cape Town (ZA)
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2003-07
Volume
38
Issue
1
Pages
123-132
ISSN
0270-9139 (ISSN-L)
DOI
10.1053/jhep.2003.50307
OpenAlex
W1963533730
Cited by
476
References
51
Citations by year
2026: 4 · 2025: 13 · 2024: 18 · 2023: 15 · 2022: 24 · 2021: 26 · 2020: 26 · 2019: 19 · 2018: 21 · 2017: 21 · 2016: 22 · 2015: 18 · 2014: 20 · 2013: 23 · 2012: 15
FWCI
17.07
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 4445 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • DIAL (Catholic University of Leuven) (submittedVersion)
  • ANU Open Research (Australian National University) (submittedVersion)
Funders
  • Medical Research Council
  • National Health and Medical Research Council (153899)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
steatohepatitis, PPARα, methionine-choline-deficient diet, CYP4A, Cyp4a14, Cyp4a10, reactive oxygen species, lipid peroxidation, Wy-14,643, peroxisomal beta-oxidation, hepatic steatosis, PPARα knockout mice
MeSH terms
Cytochrome P450 Family 4, Animals, Animal Feed, Anticholesteremic Agents, Choline Deficiency, Cytochrome P-450 Enzyme System, Fatty Acids, Fatty Liver, Female, Mixed Function Oxygenases, Liver, Male, Methionine, Mice, Inbred C57BL, Mice, Mutant Strains, Microsomes, Pyrimidines, Severity of Illness Index, Transcription Factors, Triglycerides, Lipid Peroxidation, Gene Expression Regulation, Enzymologic, Reactive Oxygen Species, Receptors, Cytoplasmic and Nuclear, Cytochrome P-450 CYP4A, Mice

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