Benign Prostate Hyperplasia Meets Liver X Receptor

Abstract

Viennois and co-workers (1) characterized Lxr knockout mice that, interestingly, develop hyperplasia of the ventral prostate. The Lxr-knockout mice have the potential to develop into a novel and very important mouse model system for benign prostate hyperplasia (BPH) with similar symptoms as in human such as hyperproliferative epithelium and hypertrophic stroma. Such an in vivo model system would be a very useful tool to analyze the development and progression of BPH and perhaps in future also as a test system for therapeutic treatment of BPH. BPH is an increasingly important health problem of man. There is a rising incidence of hyperplasia of the prostate during age. An estimated 50% of men have histological evidence of BPH at the age of 50–60 yr and 75% at the age of 80 yr, whereas in 40–50% of these men, BPH becomes clinically significant (2). The hyperplasia of the prostate may compress the urethral canal causing partial or complete constriction of the urethra. This hinders the normal flow of urine. Also the bladder may be unable to be emptied completely, causing retention of urine in the bladder and subsequently strangury associated with lower quality of life. Furthermore, incomplete voiding can lead to growth of bacteria in the bladder and an increased risk of urinary tract infection. The main two currently used medication directions of BPH address on one hand the relaxation of smooth muscles such as by -blockers and on the other hand the reduction of dihydrotestosterone production using 5 -reductase inhibitors. The latter is used to inhibit the activation of the androgen receptor (AR; NR3C4), known as a major factor promoting growth of the normal prostate and also BPH. Interestingly, herbal medications are often used for treatment of BPH. These include extracts from saw palmetto, pumpkin seed (Cucurbita pepo), pollen extracts from rye grass (Secale cereale), stinging nettle (Urtica dioica), and the African plum tree (Prunus africana; Pygeum africanum). For most of these plant extracts, the active compounds are not yet discovered. From the bark of P. africanum, specific compounds have been identified that exhibit AR-antagonistic function, indicating that the bark contains natural herbal AR antagonists (3). Testosterone promotes prostate cell proliferation; however, relatively low levels of serum testosterone are found in patients with BPH (4, 5). This indicates that also other causes of BPH must be considered. Notably, the consumption of certain fatty acids, particularly of animal origin, has been correlated with increased prostate problems. High cholesterol levels and diabetes are associated with prostate cancer development (6, 7). This may suggest that cholesterol signaling could be involved in development and progression of BPH. The liver X receptors (LXR) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXR are, as the AR, members of the nuclear receptor superfamily of ligand-controlled transcription factors. LXR bind as ligands endogenously oxidized forms of cholesterol, the oxysterols, that are present in animal fat. Two isoforms of LXR have been identified and are referred to as LXR (NR1H3) and LXR (NR1H2) classified into the subfamily 1, the thyroid hormone receptor-like members of the nuclear receptor superfamily. The activation of LXR has been shown to inhibit cardiovascular disease and reduce atherosclerosis in animal models. Liver LXR expression is crucial for whole-body cholesterol homeostasis and reverse cholesterol transport in mice. LXR agonists improve glucose tolerance in a murine model of diet-induced obesity and insulin resistance by regulating genes involved in glucose metabolism in liver and adipose tissue (8, 9).