Harashima, Shogo Yamazaki, Yuto Motomura, Naoki Ono, Yoshikiyo Omata, Kei Tezuka, Yuta Morimoto, Ryo Nakamura, Yasuhiro Satoh, Fumitoshi Suzuki, Hiroyoshi Kwon, Go Eun Choi, Man Ho Sasano, Hironobu 2024-01-19T11:34:01Z 2024-01-19T11:34:01Z 2022-06-23 2022-07 0960-0760 https://pubs.kist.re.kr/handle/201004/114910 Aldosterone-producing adenoma (APA) is histologically composed of clear and compact tumor cells. KCNJ5mutated APAs were reported to be associated with higher plasma aldosterone concentration and more abundant clear tumor cells containing lipid droplets than non-KCNJ5- mutated APAs. However, the association among cholesterol uptake and/or synthesis, cellular morphology and genotypes has remained unknown. Therefore, in order to explore these differences, 52 APA cases (KCNJ5 mt: n = 33, non-KCNJ5 mt: n = 19; ATP1A1: n = 3, ATP2B3: n = 3, CACNA1D: n = 5, CTNNB1: n = 1, tumors without any mutation above: n = 7), zona glomerulosa (ZG) tissue adjacent to APA and 10 non-pathological adrenal glands (NAs) were examined for quantitative histopathological analysis of tumor morphology and immunohistochemical analysis of cholesterol receptors (SRB1, LDL-R), cholesterol metabolic enzymes (ACAT1, ACAT2, HSL, DHCR24, StAR), and the enzymes required for steroid synthesis (CYP11A1, CYP17A, 3 beta HSD, CYP11B1, CYP11B2). Gas chromatography-mass spectrometry (GC-MS) analysis was further performed to profile cholesterol precursors and metabolites in 21 APA cases (KCNJ5 mt: n = 16, non-KCNJ5 mt: n = 5) and 14 adrenal cortex of adjacent adrenal tissues. Results demonstrated that both SR-B1 and DHCR24 were significantly lower in the ZG than in fasciculata or reticularis of NAs but LDL-R was not significantly different among them in immunohistochemical analysis. SR-B1 and DHCR24 were both significantly higher in APAs than in ZG tissue adjacent to APA. In GC-MS analysis, most cholesterol precursors and metabolites, except for lanosterol, and their metabolic ratios (= concentration of cholesterol/ precursor) were higher in APAs than in the adjacent adrenal cortex tissue. LDL-R, ACAT1/2, HSL, DHCR24 were all significantly lower in clear than in compact tumor cells of APA. LDL-R was significantly lower and cholesterol/lanosterol ratio was significantly higher in KCNJ5- mutated than non-KCNJ5- mutated APAs. We demonstrated SR-B1 mediated selective uptake of cholesterol ester and de novo cholesterol synthesis were both enhanced in APAs. In addition, cholesterol uptake and metabolism were different between clear and compact tumor cells. KCNJ5- mutated APAs were predominantly composed of clear tumor cells containing abundant cholesteryl ester but less activated LDL-R mediated uptake and increased de novo synthesis. Those findings above indicated their more pronounced functional deviation from the normal ZG cells in terms of their steroidogenic and intracellular cholesterol metabolism. English Pergamon Press Ltd. Phenotype-genotype correlation in aldosterone-producing adenomas characterized by intracellular cholesterol metabolism Article 10.1016/j.jsbmb.2022.106116 1 Journal of Steroid Biochemistry and Molecular Biology, v.221 Journal of Steroid Biochemistry and Molecular Biology 221 N scie scopus 000799734200004 Biochemistry & Molecular Biology Endocrinology & Metabolism Biochemistry & Molecular Biology Endocrinology & Metabolism Article K+ CHANNEL MUTATIONS ESTROGEN-RECEPTOR SOMATIC MUTATIONS SR-BI LIPOPROTEIN STEROIDOGENESIS PREVALENCE ATP1A1 Primary aldosteronism Aldosterone-producing adenoma Cholesterol Immunohistochemistry Mass spectrometry KCNJ5