ECE2014 Poster Presentations Male reproduction (25 abstracts)
Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit
Linda Vignozzi 1 , Sandra Filippi 2 , Paolo Comeglio 1 , Ilaria Cellai 1 , Giulia Rastrelli 1 , Annamaria Morelli 3 , Andrea Galli 1 , Farid Saad 4 , Edoardo Mannucci 5 , Luciano Adorini 6 & Mario Maggi 1
1Department Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy; 2Department NEUROFARBA, University of Florence, Florence, Italy; 3Department Experimental and Clinical Medicine, University of Florence, Florence, Italy; 4Global Medical Affairs Men’s Healthcare, Bayer Pharma AG, Berlin, Germany; 5Careggi Hospital, Critical Care, Diabetes Section, Florence, Italy; 6Intercept Pharmaceuticals, New York, New York, USA.
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 evaluating 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, with the selective farnesoid X receptor (FXR) agonist obeticholic acid (OCA), or with the anti-TNFα 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 TNFα), 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 TNFα expression and Ach response was confirmed. Accordingly, circulating levels of TNFα were increased 15-fold in HFD rabbits. testosterone and OCA dosing in HFD rabbits both significantly reduced TNFα liver expression and plasma levels, with a parallel increase of penile eNOS expression and responsiveness to Ach. Also neutralization of TNFα 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 TNFα, as indicated by treatments reducing liver and circulating TNFα levels (testosterone or OCA), or neutralizing TNFα action (infliximab), which significantly improve penile responsiveness to Ach in HFD rabbits.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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