Work

Inhibition of NPC Intracellular Cholesterol Transporter 1 Dually Regulates Aldosterone Secretion Via the Steroidogenic Acute Regulatory‐Related Lipid Transfer Domain‐3‐Voltage‐Dependent Anion Channel 1 Axis and Inositol 1,4,5‐Trisphosphate Receptor Type 3‐Calcium Signaling

Year: 2025

Type: article

Abstract: BACKGROUND: Aldosterone-producing 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-producing adenomas remains unclear. METHODS: In this study, we used quantitative proteomics and observed that NPC1 was significantly downregulated in aldosterone-producing adenoma tissues. RESULTS: 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-mitochondria interaction via STARD3-VDAC1 (steroidogenic acute regulatory-related lipid transfer domain-3-voltage-dependent 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-trisphosphate receptor type 3)-mediated endoplasmic reticulum calcium release, resulting in upregulated expression of aldosterone synthase. CONCLUSIONS: Our findings demonstrate that NPC1 downregulation represents a novel mechanism driving elevated aldosterone production, linking lysosomal-mitochondria cholesterol transport to aldosterone high production. These results suggest that NPC1 may offer a new understanding for aldosterone overproduction mechanism of aldosterone-producing adenomas.

Source: Journal of the American Heart Association

DOI: 10.1161/jaha.125.045554