The Association of Cholesterol Uptake and Synthesis with Histology and Genotype in Cortisol-Producing Adenoma (CPA).

Naoki Motomura,Yuta Tezuka,Akihiro Ito,Yasuhiro Nakamura,Hironobu Sasano,Fumitoshi Satoh,Go Eun Kwon,Ryo Morimoto,Daiki Koga,Man Ho Choi,Shogo Harashima,Yoshikiyo Ono,Kei Omata,Yuto Yamazaki,Xin Gao

doi:10.3390/ijms23042174

Abstract

Cortisol-producing adenoma (CPA) is composed of clear and compact cells. Clear cells are lipid abundant, and compact ones lipid poor but associated with higher production of steroid hormones. PRKACA mutation (PRKACA mt) in CPA patients was reported to be associated with more pronounced clinical manifestation of Cushing’s syndrome. In this study, we examined the association of histological features and genotypes with cholesterol uptake receptors and synthetic enzymes in 40 CPA cases, and with the quantitative results obtained by gas chromatography-mass spectrometry (GC-MS) analysis in 33 cases to explore their biological and clinical significance. Both cholesterol uptake receptors and synthetic enzymes were more abundant in compact cells. GC-MS analysis demonstrated that the percentage of compact cells was inversely correlated with the concentrations of cholesterol and cholesterol esters, and positively with the activity of cholesterol biosynthesis from cholesterol esters. In addition, hormone-sensitive lipase (HSL), which catalyzes cholesterol biosynthesis from cholesterol esters, tended to be more abundant in compact cells of PRKACA mt CPAs. These results demonstrated that both cholesterol uptake and biosynthesis were more pronounced in compact cells in CPA. In addition, more pronounced HSL expression in compact cells of PRKACA mt CPA could contribute to their more pronounced clinical manifestation.

Highlights

Cortisol is synthesized from cholesterol through the cascades of steroidogenic enzymes including CYP17A1 and CYP11B1 in the zona fasciculata cells of human adrenal cortex
Results of in vitro studies using a human adrenocortical carcinoma cell line demonstrated that steroidogenic factor 1, which played a key role in enhancing expression of many essential steroidogenic enzymes, activated Hormone-sensitive lipase (HSL) transcription [9,10]. 24-Dehydrocholesterol reductase (DHCR24) is one of the key enzymes in the de novo cholesterol synthesizing pathway and catalyzes the cholesterol synthesis from acetyl-CoA [1]
London E et al recently reported that extracellular cholesterol uptake via low density lipoprotein receptor (LDL-R) and intracellular cholesterol synthesis through de novo pathways were both increased, and cholesterol efflux was decreased in Cortisol-producing adenoma (CPA) compared to bilateral adrenal hyperplasia (BAH), which indicated that CPA could correspond to “cholesterol-starved tissues” [13]

Summary

Introduction

Cortisol is synthesized from cholesterol through the cascades of steroidogenic enzymes including CYP17A1 and CYP11B1 in the zona fasciculata cells of human adrenal cortex. Intracellular free cholesterol is generally provided by three pathways: uptake of plasma cholesterols, metabolism of intracellularly stored cholesterol esters, and de novo biosynthesis [1]. SR-B1 is known to mediate the selective uptake of cholesterol esters into the cells in steroidogenesis [3], and its deficiency was reported to result in decreased overall steroid production [4]. Hormone-sensitive lipase (HSL) is responsible for the biosynthesis of cholesterol from cholesterol esters, and both acyl-CoA:cholesterol acyltransferase 1 (ACAT1) and acyl-CoA:cholesterol acyltransferase 2 (ACAT2) catalyze the conversion of free cholesterol into cholesterol esters and play important roles in maintaining the homeostasis of the intracellular cholesterol levels [1,5]. Results of in vitro studies using a human adrenocortical carcinoma cell line demonstrated that steroidogenic factor 1, which played a key role in enhancing expression of many essential steroidogenic enzymes, activated HSL transcription [9,10]. Results of in vitro studies using a human adrenocortical carcinoma cell line demonstrated that steroidogenic factor 1, which played a key role in enhancing expression of many essential steroidogenic enzymes, activated HSL transcription [9,10]. 24-Dehydrocholesterol reductase (DHCR24) is one of the key enzymes in the de novo cholesterol synthesizing pathway and catalyzes the cholesterol synthesis from acetyl-CoA [1]

Methods

Results

Discussion

Conclusion