{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T21:07:04Z","timestamp":1783804024594,"version":"3.55.0"},"reference-count":64,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical and health technology project of Hangzhou","award":["B20220042"],"award-info":[{"award-number":["B20220042"]}]},{"name":"Zhejiang Medical Association Clinical Medical Research Special Fund of Project","award":["2022ZYC-A146"],"award-info":[{"award-number":["2022ZYC-A146"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec>\n<jats:title>\nPurpose\n<\/jats:title>\n<jats:p>This study mimics the metabolic environment of metabolic dysfunction-associated steatotic liver disease (MASLD) and diabetic mellitus (DM) to investigate the function of <jats:italic>BRCA1<\/jats:italic> in regulating glucose and lipid metabolism in hepatocytes under high glucose (HG) settings.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>\nMethods\n<\/jats:title>\n<jats:p>MASLD and DM-related datasets (GSE89632, GSE95849) were screened for overlapping genes, Protein-Protein Interaction (PPI) network and enrichment analyses were performed. Then, quantitative real-time polymerase chain reaction (qRT-PCR), Western Blotting (WB), and enzymatic colorimetric assays to examine the expression changes of <jats:italic>BRCA1<\/jats:italic> in mouse primary hepatocytes under HG conditions and the impact of the combined PI3K\/Akt signaling pathway on key metabolic markers of gluconeogenesis and lipid metabolism.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>\nResults\n<\/jats:title>\n<jats:p>Our study identified seven key overlapping genes (<jats:italic>AURKA<\/jats:italic>, <jats:italic>BRCA1<\/jats:italic>, <jats:italic>ISG15<\/jats:italic>, <jats:italic>NUSAP1<\/jats:italic>, <jats:italic>OAS1<\/jats:italic>, <jats:italic>RSAD2<\/jats:italic>, <jats:italic>TLR7<\/jats:italic>) between MASLD and DM. Experiments found that when <jats:italic>BRCA1<\/jats:italic> was overexpressed in mouse primary hepatocytes, intracellular triglyceride content and lipid metabolism-related biomarkers (such as PEPCK, SREBP-1c, G6Pase, and FAS) were significantly increased in HG circumstances. However, the knockdown of <jats:italic>BRCA1<\/jats:italic> reduced the expression of these indicators. Besides, we also observed that under HG conditions, the expression of proteins linked to the PI3K\/Akt signaling pathway was negatively regulated by <jats:italic>BRCA1<\/jats:italic> expression. Moreover, TG content and expression of lipid metabolism markers are also regulated by <jats:italic>BRCA1<\/jats:italic> and PI3K\/Akt pathway inhibitor Ly294002.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>\nConclusion\n<\/jats:title>\n<jats:p>As a key regulator of hepatocyte metabolism under HG conditions, <jats:italic>BRCA1<\/jats:italic> can participate in regulating glucose and lipid metabolism in mouse primary hepatocytes through the PI3K\/AKT signaling pathway, which be able to become a possible remedy strategy for DM with MASLD.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0318696","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T20:01:12Z","timestamp":1743019272000},"page":"e0318696","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["BRCA1 regulates glucose and lipid metabolism in diabetes mellitus with metabolic dysfunction-associated steatotic liver disease via the PI3K\/Akt signaling 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