De novo lipid synthesis in the pathogenesis of benign prostatic hyperplasia.
Abstract
Introduction:
Benign prostatic hyperplasia (BPH) is the most prevalent urological condition in older men, affecting ~ 50% of men above the age of 50. As the prostate gland enlarges around the urethra, urine flow is obstructed, driving a collection of deteriorating symptoms known as Lower Urinary Tract Symptoms (LUTS). BPH is known to be driven by an age-related steroid hormone imbalance and inflammation. Steroid hormone imbalance can be reproduced in mice via testosterone and estradiol treatment (T+E2). In this model, we previously identified foam cell differentiation, a lipid-laden macrophage phenotype, specifically in the lumen. Foam cells indicate lipid dysregulation, but the source of excess lipids in the BPH prostate is unknown. Therefore, in this study, we assessed the gene expression pattern of genes of the de novo lipid synthesis pathway in the T+E2 model.
Methods:
Male C57BL/6J mice were implanted with pellets containing 25 mg (T) and 2.5 mg (E2), and their ventral prostates were collected two weeks later. Cells were then dissociated with cold protease and loaded on Chromium Next GEM (7000 cells/sample). Each sample was sequenced on NextSeq2000 at 100 million reads/sample. In situ hybridization (ISH) was performed to confirm scRNA-seq results using probes for FASN. The effect of E2 (0.1-100 nM) in vitro was tested on BPH-1 cells.
Results:
The scRNA-seq analysis of T+E2 ventral prostates identified two luminal, a basal, a proliferating and a progenitor epithelial cell cluster. Expressional analysis indicated an increase in the majority of genes of the de novo lipid synthesis pathway (i.e., Fasn, Scd-1, Acly, and Acat1/2) in most epithelial clusters. Increased Fasn expression was confirmed via ISH (p < 0.01). Expression of genes of the de novo lipid synthesis pathway was also explored in BPH-1 cells in response to E2.
Conclusions:
Our findings indicate a potential role for lipid dysregulation and an increase in de novo lipid synthesis in the pathogenesis of BPH regulated by steroid hormone imbalance. Our future studies aim to determine whether E2-treated epithelial cells can directly stimulate foam cell formation in co-culture models.