{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:55:21Z","timestamp":1790920521162,"version":"4.1.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Cholesterol homeostasis is tightly regulated through hepatic synthesis, intestinal absorption, and biliary excretion, with bile acids serving as critical regulators of cholesterol catabolism. Dysregulated cholesterol metabolism and bile acid imbalance are hallmarks of non-alcoholic fatty liver disease (NAFLD), contributing to hepatic lipid accumulation and disease progression. Dendrobine (DNE), a bioactive alkaloid from\n                      <jats:italic>Dendrobium nobile<\/jats:italic>\n                      , has emerged as a potential therapeutic candidate for lipid metabolic disorders.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      C57BL\/6J mice were fed a high-fat diet to establish an NAFLD model, followed by DNE administration. Hepatic steatosis and cholesterol deposition were evaluated\n                      <jats:italic>via<\/jats:italic>\n                      histology and biochemical assays; bile acid profiles were quantified by LC-MS\/MS. Gene and protein expression were analyzed using RT-qPCR and Western blotting.\n                      <jats:italic>In vitro<\/jats:italic>\n                      studies using cholesterol-laden HepG2 cells further explored DNE\u2019s mechanisms, validated by specific pharmacological agonists and inhibitors of the Farnesoid X receptor (FXR) and liver X receptor (LXR) pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      DNE significantly ameliorated hepatic steatosis and reduced cholesterol accumulation in HFD-induced NAFLD mice. LC-MS\/MS analysis revealed that DNE substantially expanded the bile acid (BA) pool in the liver, bile, and ileum. Mechanistically, DNE comprehensively modulated cholesterol absorption, biotransformation, and transport by modulating the FXR and LXR signaling pathways. It robustly upregulated key genes involved in BA synthesis (e.g.,\n                      <jats:italic>Cyp7a1<\/jats:italic>\n                      ) and efflux, while downregulating transporters responsible for BA and cholesterol reuptake (e.g.,\n                      <jats:italic>Ntcp<\/jats:italic>\n                      ,\n                      <jats:italic>Npc1l1<\/jats:italic>\n                      ).\n                      <jats:italic>In vitro<\/jats:italic>\n                      validation using specific pharmacological agonists and antagonists further confirmed that DNE upregulates\n                      <jats:italic>CYP7A1<\/jats:italic>\n                      and promotes BA synthesis\n                      <jats:italic>via<\/jats:italic>\n                      a dual FXR\/LXR\u03b1-dependent regulatory network.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings suggest that DNE modulates cholesterol homeostasis and alleviates NAFLD in conjunction with BA synthesis, transport, and absorption, in a manner associated with the FXR\/LXR\u03b1 regulatory network, presenting a promising therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1875005","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:35:24Z","timestamp":1790919324000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dendrobine\u2019s mechanism: alleviating cholesterol metabolism disorders via FXR\/LXR modulation in NAFLD mouse livers"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhi","family":"Chen","sequence":"first","affiliation":[{"name":"Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, Guizhou Engineering Research Center of Industrial Key-technology for 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