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

Abstract

a b s t r a c tA 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-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 rabhttp://dx

Nonalcoholic Fatty Liver Disease is Associated with Erectile Dysfunction: A Prospective Pilot Study

“…In a recent study on the nongenomic, high-fat dieteinduced model of MetS in rabbits (characterized by hyperglycemia, glucose intolerance, hypercholesterolemia, hypertriglyceridemia, hypertension, increased visceral fat mass, hypogonadotropic hypogonadism, and NASH) that closely resembles the human MetS phenotype, MetS-induced NASH was suggested to play an active role in the pathogenesis of ED, likely via TNFa. 19 Moreover, treatment of those rabbits with infliximab, a selective antiTNFa antibody and obeticholic acid, a farnesoid X receptor agonist resulted in amelioration of liver damage and improvement of penile responsiveness to acetylcholine. 19 The role of increased TNFa, a proinflammatory cytokine, in NAFLD has long been studied by many researchers including our group.…”

“…19 Moreover, treatment of those rabbits with infliximab, a selective antiTNFa antibody and obeticholic acid, a farnesoid X receptor agonist resulted in amelioration of liver damage and improvement of penile responsiveness to acetylcholine. 19 The role of increased TNFa, a proinflammatory cytokine, in NAFLD has long been studied by many researchers including our group. 20 Hence, an ongoing hepatic inflammation, as reflected in our patients' liver biopsies may count for the triggering factor of the accompanying vascular disease in NAFLD patients.…”

“…Nevertheless, the lack of TNFa measurements in the current study population may be taken as a limitation of our study after the recognition of its link with ED by the recent animal study. 19 …”

Testosterone therapy in men with Crohn’s disease improves the clinical course of the disease: data from long-term observational registry study

“…In addition, hsCRP [38] and leukocyte count were measured. Liver enzymes were determined since the liver is the source of TNF-α [39].…”

Benign prostatic hyperplasia and metabolic syndrome: the expanding evidences of a new disease of aging male

“…Insulin resistance is the underlying mechanism of metabolic syndrome and is also the most prevalent risk factor for NAFLD, a condition strongly associated with hepatic and adipose tissue insulin resistance, as well as reduced wholebody insulin sensitivity Interestingly, MetS induced inflammation within the liver, also known as steato-hepatitis, has been very recently elucidated in an experimental study in the rabbit [14]. Surprisingly, a recent cross-sectional study showed a new link between the presence of BPH/LUTS, MetS and NAFLD, demonstrating a 2.0-fold risk of having moderate-severe LUTS in men with both manifestation (OR ¼ 2.10, p50.01) [15].…”