Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit.
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 (T), 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. T and OCA dosing in HFD rabbits both 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 (T or OCA), or neutralizing TNFα action (infliximab), which significantly improve penile responsiveness to Ach in HFD rabbits.
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy.
Linda
L
Vignozzi
Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Department of Neuroscience, Drug Research and Child Care, University of Florence, Florence, Italy.
Sandra
S
Filippi
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy.
Paolo
P
Comeglio
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy.
Ilaria
I
Cellai
Department of Experimental and Clinical Medicine, University of Florence, Italy.
Erica
E
Sarchielli
Department of Experimental and Clinical Medicine, University of Florence, Italy.
Annamaria
A
Morelli
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy.
Giulia
G
Rastrelli
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy.
Elena
E
Maneschi
Gastroenterology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy.
Andrea
A
Galli
Department of Experimental and Clinical Medicine, University of Florence, Italy.
Gabriella Barbara
GB
Vannelli
Global Medical Affairs Men's Healthcare, Bayer Pharma AG, Muellerstrasse 178, Berlin, Germany.
Farid
F
Saad
Diabetes Section Geriatric Unit, Department of Critical Care, University of Florence, Italy.
Edoardo
E
Mannucci
Intercept Pharmaceuticals, 18 Desbrosses Street, New York, NY 10013, USA.
Luciano
L
Adorini
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy. Electronic address: mario.maggi@unifi.it.
Mario
M
Maggi
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000009:adverse effects*; D007172:Erectile Dysfunction / Q000150:complications* / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D005234:Fatty Liver / Q000150:complications* / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D000069285:Infliximab; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications* / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D010413:Penis / Q000187:drug effects / Q000502:physiology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D013739:Testosterone / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000069058:Vardenafil Dihydrochloride; D000099150:Receptor, Farnesoid X-Activated
D000109:Acetylcholine; D000911:Antibodies, Monoclonal; D002635:Chenodeoxycholic Acid; D004041:Dietary Fats; D007093:Imidazoles; D000069285:Infliximab; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D018160:Receptors, Cytoplasmic and Nuclear; D013450:Sulfones; D013739:Testosterone; D014227:Triazines; D014409:Tumor Necrosis Factor-alpha; D000069058:Vardenafil Dihydrochloride; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid
Hypogonadism; Infliximab; OCA; TNFα; Testosterone