RESUMO
Benign prostatic hyperplasia (BPH) is one of the major chronic complications of type 2 diabetes mellitus (T2DM), and sex steroid hormones are common risk factors for the occurrence of T2DM and BPH. The profiles of sex steroid hormones are simultaneously quantified by LC-MS/MS in the clinical serum of patients, including simple BPH patients, newly diagnosed T2DM patients, T2DM complicated with BPH patients and matched healthy individuals. The G protein-coupled estrogen receptor (GPER) inhibitor G15, GPER knockdown lentivirus, the YAP1 inhibitor verteporfin, YAP1 knockdown/overexpression lentivirus, targeted metabolomics analysis, and Co-IP assays are used to investigate the molecular mechanisms of the disrupted sex steroid hormones homeostasis in the pathological process of T2DM complicated with BPH. The homeostasis of sex steroid hormone is disrupted in the serum of patients, accompanying with the proliferated prostatic epithelial cells (PECs). The sex steroid hormone metabolic profiles of T2DM patients complicated with BPH have the greatest degrees of separation from those of healthy individuals. Elevated 17ß-estradiol (E2) is the key contributor to the disrupted sex steroid hormone homeostasis, and is significantly positively related to the clinical characteristics of T2DM patients complicated with BPH. Activating GPER by E2 via Hippo-YAP1 signaling exacerbates high glucose (HG)-induced PECs proliferation through the formation of the YAP1-TEAD4 heterodimer. Knockdown or inhibition of GPER-mediated Hippo-YAP1 signaling suppresses PECs proliferation in HG and E2 co-treated BPH-1 cells. The anti-proliferative effects of verteporfin, an inhibitor of YAP1, are blocked by YAP1 overexpression in HG and E2 co-treated BPH-1 cells. Inactivating E2/GPER/Hippo/YAP1 signaling may be effective at delaying the progression of T2DM complicated with BPH by inhibiting PECs proliferation.
RESUMO
Non-alcoholic fatty liver disease (NAFLD) was a chronic complication of type 2 diabetes mellitus (T2DM), and this comorbid disease lacked therapeutic drugs. Semen Ziziphi Spinosae (SZS) was the seed of Ziziphus jujuba var. Spinosa (Bunge) Hu ex H.F. Chow, and it could alleviate the symptoms of T2DM patients. As a triterpene saponin, Jujuboside A (Ju A) was the main active substance isolated from SZS and could improve hyperglycemia of diabetic mice. However, it was still unknown whether Ju A has protective effects on T2DM-associated NAFLD. Our study showed that Ju A attenuated T2DM-associated liver damage by alleviating hepatic lipid accumulation, inflammatory response, and oxidative stress in the liver of db/db mice, and high glucose (HG) and free fatty acid (FFA) co-stimulated human hepatocellular carcinomas (HepG2) cells. Along with the improved hyperglycemia and liver injury, Ju A restrained Yin Yang 1 (YY1)/cytochrome P450 2E1 (CYP2E1) signaling in vivo and in vitro. YY1 overexpression intercepted the protective effects of Ju A on T2DM-induced liver injury via promoting hepatic lipid accumulation, inflammatory response, and oxidative stress. While, the blocking effect of YY1 overexpression on Ju A's hepatoprotective effect was counteracted by further treatment of CYP2E1 specific inhibitor diethyldithiocarbamate (DDC) in vitro. In-depth mechanism research showed that Ju A through YY1/CYP2E1 signaling promoted hepatic fatty acid ß-oxidation, and inhibited inflammatory response and oxidative stress by activating peroxisome proliferator-activated receptor alpha (PPARα), leading to the improvement of T2DM-associated NAFLD. Ju A might be a potential agent in the treatment and health care of T2DM-associated liver disease, especially NAFLD.