{
  "abstract": "Background: A high-fat diet (HFD) is closely associated with the progression of ulcerative colitis (UC). However, the underlying mechanisms, particularly the interplay among lipid metabolic disturbances, mitochondrial damage, and intestinal barrier dysfunction, remain poorly defined. This study aimed to elucidate the molecular mechanisms by which HFD exacerbates DSS-induced UC, with a focus on the role of the AMPK/PPARα axis in mediating lipotoxicity and mitochondrial dysfunction that promote UC progression. Methods: A murine UC model was established in C57BL/6 mice by HFD feeding combined with DSS administration, along with an in vitro co-stimulation system using Caco-2 cells exposed to palmitic acid (PA) and lipopolysaccharide (LPS). Pathological phenotypes and molecular pathway alterations were systematically evaluated by hematoxylin and eosin (HE) staining, transmission electron microscopy (TEM), molecular biological techniques, and intervention with the specific AMPK agonist AICAR. Results: HFD significantly exacerbated DSS-induced colitis, as manifested by rapid weight loss, elevated disease activity index, and destruction of mucosal tissue architecture. Mechanistically, HFD led to intestinal epithelial lipid accumulation and gut microbiota dysbiosis, which synergistically triggered oxidative stress and paradoxically suppressed AMPK phosphorylation (p-AMPK). AMPK inactivation downregulates PPARα and its downstream fatty acid oxidation enzymes (CPT1A and ACOX1), exacerbating lipotoxicity and mitochondrial ultrastructural damage. Concurrently, decreased expression of key respiratory chain subunits (NDUFS2 and MTCO2) ultimately culminates in an energy crisis. Notably, pharmacological activation of AMPK using AICAR effectively reversed p-AMPK inhibition, restored PPARα expression, and ameliorated intestinal barrier function, demonstrating that the AMPK pathway serves as a critical pathogenic driver. Conclusion: HFD, through lipotoxicity and microbiota-derived pro-inflammatory signals, induces paradoxical inactivation of the intestinal epithelial AMPK/PPARα axis, which subsequently blocks fatty acid oxidation, provokes mitochondrial dysfunction and ATP depletion, and ultimately leads to breakdown of the intestinal barrier. This study uncovers a novel mechanistic link among metabolism, mitochondrial function, and gut barrier integrity, providing a solid theoretical and experimental foundation for precision metabolic reprogramming-based therapies in UC patients with metabolic derangements.",
  "abstract_shown": true,
  "affiliations": [
    "The First Department of Gastroenterology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Huiyue Pan"
    },
    {
      "name": "Leilei Zhai"
    },
    {
      "name": "Shupeng Zhao"
    },
    {
      "name": "Ziyi Guo"
    },
    {
      "name": "Ping Yao"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/agacrvvwygm9b.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pone.0358354",
  "fulltext_url": null,
  "id": "agacrvvwygm9b",
  "issns": [
    "1932-6203"
  ],
  "landing_url": "https://doi.org/10.1371/journal.pone.0358354",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1311|Inflammatory Bowel Disease"
    ],
    [
      "plos",
      "/Biology and life sciences/Anatomy/Digestive system/Gastrointestinal tract"
    ],
    [
      "plos",
      "/Biology and life sciences/Anatomy/Digestive system/Gastrointestinal tract/Colon"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Bioenergetics/Energy-producing organelles/Mitochondria"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Lipids/Lipid metabolism"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Metabolism/Lipid metabolism"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular structures and organelles/Energy-producing organelles/Mitochondria"
    ],
    [
      "plos",
      "/Biology and life sciences/Nutrition/Diet"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Bacteria/Gut bacteria"
    ],
    [
      "plos",
      "/Medicine and health sciences/Anatomy/Digestive system/Gastrointestinal tract"
    ],
    [
      "plos",
      "/Medicine and health sciences/Anatomy/Digestive system/Gastrointestinal tract/Colon"
    ],
    [
      "plos",
      "/Medicine and health sciences/Gastroenterology and hepatology/Inflammatory bowel disease/Colitis/Ulcerative colitis"
    ],
    [
      "plos",
      "/Medicine and health sciences/Nutrition/Diet"
    ],
    [
      "plos",
      "/Research and analysis methods/Biological cultures/Cell lines/Caco-2 cells"
    ]
  ],
  "openalex": "W7220839738",
  "pdf_url": "https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0358354&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-07",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/agacrvvwygm9b.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:30Z",
      "native_id": "10.1371/journal.pone.0358354",
      "source": "plos",
      "url": "https://doi.org/10.1371/journal.pone.0358354"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "plos:nutrition",
      "subfield": "nutrition"
    },
    {
      "field": "medicine",
      "origin": "plos:anatomy",
      "subfield": "physiology"
    }
  ],
  "title": "Impaired fatty acid oxidation and mitochondrial injury mediated by the AMPK/PPARα pathway: A key mechanism in high-fat diet-aggravated ulcerative colitis",
  "title_text": "Impaired fatty acid oxidation and mitochondrial injury mediated by the AMPK/PPARα pathway: A key mechanism in high-fat diet-aggravated ulcerative colitis",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:30Z",
  "url": "https://research.draconitic.com/paper/agacrvvwygm9b",
  "venue": "PLOS One",
  "versions": []
}