A pathogenic link between erectile dysfunction (ED) and metabolic syndrome (MetS) is now well established. Nonalcoholic steatohepatitis (NASH), the hepatic hallmark of MetS, is regarded as an active player in the pathogenesis of MetS-associated cardiovascular disease (CVD). This study was aimed at valuating the relationship between MetS-induced NASH and penile dysfunction. We used a non-genomic, high fat diet (HFD)-induced, rabbit model of MetS, and treated HFD rabbits with testosterone (T), with the selective farnesoid X receptor (FXR) agonist obeticholic acid (OCA), or with the anti-TNFa mAb infliximab. Rabbits fed a regular diet were used as controls. Liver histomorphological and gene expression analysis demonstrated NASH in HFD rabbits. Several genes related to inflammation (including TNFa), activation of stellate cells, fibrosis, and lipid metabolism parameters were negatively associated to maximal acetylcholine (Ach)-induced relaxation in penis. When all these putative liver determinants of penile Ach responsiveness were tested as covariates in a multivariate model, only the association between hepatic TNFa expression and Ach response was confirmed. Accordingly, circulating levels of TNFa were increased 15-fold in HFD rabbits. T and OCA dosing in HFD rabbits both reduced TNFa liver expression and plasma levels, with a parallel increase of penile eNOS expression and responsiveness to Ach. Also neutralization of TNFa with infliximab treatment fully normalized HFD-induced hypo-responsiveness to Ach, as well as responsiveness to vardenafil, a phosphodiesterase type 5 inhibitor. Thus, MetS-induced NASH in HFD rabbits plays an active role in the pathogenesis of ED, likely through TNFa, as indicated by treatments reducing liver and circulating TNFa levels (T or OCA), or neutralizing TNFa action (infliximab), which significantly improve penile responsiveness to Ach in HFD rabbits.

Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit / Vignozzi L; Filippi S; Comeglio P; Cellai I; Sarchielli E; Morelli A; Rastrelli G; Maneschi E; Galli A; Vannelli GB; Saad F; Mannucci E; Adorini L; Maggi M.. - In: MOLECULAR AND CELLULAR ENDOCRINOLOGY. - ISSN 0303-7207. - STAMPA. - 384:(2014), pp. 143-154. [10.1016/j.mce.2014.01.014]

Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit.

VIGNOZZI, LINDA;FILIPPI, SANDRA;COMEGLIO, PAOLO;CELLAI, ILARIA;SARCHIELLI, ERICA;MORELLI, ANNAMARIA;RASTRELLI, GIULIA;MANESCHI, ELENA;GALLI, ANDREA;VANNELLI, GABRIELLA;MANNUCCI, EDOARDO;MAGGI, MARIO
2014

Abstract

A pathogenic link between erectile dysfunction (ED) and metabolic syndrome (MetS) is now well established. Nonalcoholic steatohepatitis (NASH), the hepatic hallmark of MetS, is regarded as an active player in the pathogenesis of MetS-associated cardiovascular disease (CVD). This study was aimed at valuating the relationship between MetS-induced NASH and penile dysfunction. We used a non-genomic, high fat diet (HFD)-induced, rabbit model of MetS, and treated HFD rabbits with testosterone (T), with the selective farnesoid X receptor (FXR) agonist obeticholic acid (OCA), or with the anti-TNFa mAb infliximab. Rabbits fed a regular diet were used as controls. Liver histomorphological and gene expression analysis demonstrated NASH in HFD rabbits. Several genes related to inflammation (including TNFa), activation of stellate cells, fibrosis, and lipid metabolism parameters were negatively associated to maximal acetylcholine (Ach)-induced relaxation in penis. When all these putative liver determinants of penile Ach responsiveness were tested as covariates in a multivariate model, only the association between hepatic TNFa expression and Ach response was confirmed. Accordingly, circulating levels of TNFa were increased 15-fold in HFD rabbits. T and OCA dosing in HFD rabbits both reduced TNFa liver expression and plasma levels, with a parallel increase of penile eNOS expression and responsiveness to Ach. Also neutralization of TNFa with infliximab treatment fully normalized HFD-induced hypo-responsiveness to Ach, as well as responsiveness to vardenafil, a phosphodiesterase type 5 inhibitor. Thus, MetS-induced NASH in HFD rabbits plays an active role in the pathogenesis of ED, likely through TNFa, as indicated by treatments reducing liver and circulating TNFa levels (T or OCA), or neutralizing TNFa action (infliximab), which significantly improve penile responsiveness to Ach in HFD rabbits.
2014
384
143
154
Vignozzi L; Filippi S; Comeglio P; Cellai I; Sarchielli E; Morelli A; Rastrelli G; Maneschi E; Galli A; Vannelli GB; Saad F; Mannucci E; Adorini L; ...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/927932
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