{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:03:29Z","timestamp":1790643809482,"version":"4.1.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Aldosterone\u2010producing adenomas, a prevalent cause of endocrine hypertension, arise from uncontrolled aldosterone production. NPC1 (NPC intracellular cholesterol transporter 1) is a cholesterol transporter located on the lysosomal limiting membrane. Although cholesterol serves as the primary precursor for aldosterone synthesis, the mechanism governing its supply and metabolism within aldosterone\u2010producing adenomas remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">In this study, we used quantitative proteomics and observed that NPC1 was significantly downregulated in aldosterone\u2010producing adenoma tissues.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">Liquid chromatography\/tandem mass spectrometry analysis found that inhibition of NPC1 increased aldosterone secretion in H295R cells. Mechanistically, NPC1 deficiency promoted aldosterone production through 2 pathways: (1) immunofluorescence and coimmunoprecipitation experiments confirmed that NPC1 deficiency enhanced lysosome\u2010mitochondria interaction via STARD3\u2010VDAC1 (steroidogenic acute regulatory\u2010related lipid transfer domain\u20103\u2010voltage\u2010dependent anion channel 1), leading to mitochondrial cholesterol overload; and (2) Western Blot and calcium measurement showed that NPC1 deficiency activated of cytoplasmic calcium signaling through IP3R3 (inositol 1,4,5\u2010trisphosphate receptor type 3)\u2010mediated endoplasmic reticulum calcium release, resulting in upregulated expression of aldosterone synthase.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Our findings demonstrate that NPC1 downregulation represents a novel mechanism driving elevated aldosterone production, linking lysosomal\u2010mitochondria cholesterol transport to aldosterone high production. These results suggest that NPC1 may offer a new understanding for aldosterone overproduction mechanism of aldosterone\u2010producing adenomas.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.045554","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T10:49:13Z","timestamp":1761648553000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Inhibition of NPC Intracellular Cholesterol Transporter 1 Dually Regulates Aldosterone Secretion Via the Steroidogenic Acute Regulatory\u2010Related Lipid Transfer Domain\u20103\u2010Voltage\u2010Dependent Anion Channel 1 Axis and Inositol 1,4,5\u2010Trisphosphate Receptor Type 3\u2010Calcium Signaling"],"prefix":"10.1161","volume":"14","author":[{"given":"Jun","family":"Chen","sequence":"first","affiliation":[{"name":"the First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, 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