{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:58:41Z","timestamp":1791395921491,"version":"4.3.3"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Tianshan Talents Medical and Health Leading Talents Program","award":["TSYC202401A022"],"award-info":[{"award-number":["TSYC202401A022"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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\/PPAR\u03b1 axis in mediating lipotoxicity and mitochondrial dysfunction that promote UC progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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 PPAR\u03b1 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 PPAR\u03b1 expression, and ameliorated intestinal barrier function, demonstrating that the AMPK pathway serves as a critical pathogenic driver.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>HFD, through lipotoxicity and microbiota-derived pro-inflammatory signals, induces paradoxical inactivation of the intestinal epithelial AMPK\/PPAR\u03b1 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0358354","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:32:32Z","timestamp":1791394352000},"page":"e0358354","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impaired fatty acid oxidation and mitochondrial injury mediated by the AMPK\/PPAR\u03b1 pathway: A key mechanism in high-fat diet-aggravated ulcerative colitis"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2809-7596","authenticated-orcid":true,"given":"Huiyue","family":"Pan","sequence":"first","affiliation":[{"name":"The First 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