Intracellular Cholesterol Metabolism in Aldosterone-Producing Adenoma.~A Possible Association With Cellular Morphometry and Genotype~

Abstract

Introduction: Primary aldosteronism (PA) is the most common cause of secondary hypertension. More than 70% of APAs have been reported to have KCNJ5 somatic mutation in Asian countiries. Patients with KCNJ5 mutated APAs generally harbor high plasma aldosterone concentration (PAC), and are mainly composed of clear tumor cells containing abundant lipid droplets. However, an association among intracellular cholesterol metabolism, morphological features and genotypes in tumor cells has remained virtually unknown.[Materials and methods]Three cholesterol receptors (SR-B1, LDL-R, VLDL-R) were immunolocakized in 25 APA cases (KCNJ5 mt: n= 15, WT: n=10) who underwent adrenalectomy at Tohoku University Hospital. Image analysis software (HALO, India Labs) was used to quantitatively analyze the intracellular localization and immunoreactivity and expored their correlation with genotype and clinical factors.[Results]LDL-R immunoreactivity was significantly lower in KCNJ5 mt group than WT group (P = 0.0369). In KCNJ5 mt group, a significant correlation was detected between LDL-R immunoreactivity and CYP11B2 (Aldosterone synthase), (P = 0.0271, ρ = 0.5684) but not in WT group. In addition, LDL-R immunoreactivity was significantly inversely correlated with tumor size (P = 0.0142, ρ = -0.6176) and PAC (P = <0.001, ρ = -0.7179) in mt group as well as in whole APA cases.[Discussion]This is the first study to compare cholesterol receptor expression profiles with morphological tumor cell subtype, genotype, and clinical data in APAs. Results indicated that KCNJ5 mt APAabundantly stored cholesterol ester in their cytoplasm and cholesterol uptake was less activated, resulting In rather efficient aldosterone biosynthesis in tumor cells. In addition, a significant correlation was detected between LDL-R and CYP11B2 with the abundant localization of LDL-R in tumor cells. Therefore, LDL-R could be a predominant resource of plasma lipoprotein uptake in aldosterone-producing tumor cells, especially for KCNJ5mt APAs.