There are increasing evidence that indicates positive relationship between metabolic syndrome and symptom severity in benign prostatic hyperplasia (BPH). However, the underlying pathophysiological mechanism is still unclear. Metabolic syndrome is known to induce oxidative stress in several tissues which can lead to chronic inflammation (1). Also, It has been reported that oxidative stress can interfere the autophagic process, resulting in augumentation of obesity-related pathologies in multiple organs (2) and that SQSTM1/p62, which is an autophagy receptor, has anti-inflammatory effect (3). However, it is uncertain whether autophagic system is inhibited in the prostate involved in obesity or not. Therefore we investigated changes in gene expression of SQSTM1/p62 and its related inflammatory cytokines in the prostate using high fat diet induced obesity rat model.

Male Wistar rats (8 weeks old) were divided into a normal diet group (ND, n=5) and a high fat diet induced obesity group (HFD, n=5). The high fat diet contains 32% fat. After the rats were maintained on these diets for 12 weeks, voiding behavior analysis was performed by metabolic cage system to analyze single voided volume and voiding frequency. The prostate was harvested after voiding behavioral analysis to investigate changes in prostate volume, histological profile and mRNA expression of SQSTM1/p62, IL1β, NLRP3, TGFβ1 by qPCR. Furthermore, to detect localization of autophagosome expression in the prostate, immunohistostaining for LC3 (Microtubule-associated protein 1 light chain 3) was performed.

Prostate volume was significantly increased in HFD compared to ND. In voiding behavior analysis there was significantly decreased single voided volume in HFD compared to ND. Gene expression of SQSTM1/p62 was significantly decreased in HFD compared to ND whereas mRNA expression level of IL1β, NLRP3, TGFβ1 was significantly increased in HFD compared to ND. Hematoxylin and eosin staining showed increased stromal infiltration of inflammatory cells as well as collagen fiber in HFD compared to ND. In immunohistostaining, a positive immunoreactivity was shown in inflammatory cell in the prostate in both group.

Rats with high fat diet exhibited not only significantly increased prostate volume and prostatic inflammation as evidenced by inflammatory cell infiltration in HE staining but also bladder over activity as evidenced by significantly decreased single voided volume compared to rats with normal diet. These results indicates high fat diet induced obesity can induce BPH in association prostatic inflammation, leading to bladder symptoms. Furthermore, in molecular expression profiles, there were significant upregulation in gene expression of  IL1β, NLRP3, TGFβ1 whereas SQSTM1/p62 was significantly downregulated in HFD group compared to ND in association with LC localization in inflammatory cell in the prostate. These results suggested that oxidative stress by obesity induced activation of NLRP3 inflammasome as evidenced by increased expression  of IL1β, which is an downstream cytokine, which lead to tissue inflammation and fibrosis in association with TGFβ1 upregulation. Furthermore, autophagic dysregulation in inflammatory cell is potentially implicated to chronic inflammation in the prostate because  SQSTM1/p62, which is autophagic receptor, is reported to have anti-inflammatory effect.

High fat diet induced obesity model showed bladder over activity as well as prostatic enlargement with chronic inflammation in association with downregulation of SQSTM1/p62 and inflammatory cytokines, suggesting that autophagic dysregulation induced by obesity can lead BPH in association with prostatic inflammation. Therefore SQSTM1/p62 could be an potential molecular target of BPH with bladder symptoms.

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