title: Ovarian senescence increases liver fibrosis in humans and zebrafish with steatosis.
abstract: Contrasting data exist on the effect of gender and menopause on the susceptibility, development and liver damage progression in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether menopause is associated with the severity of liver fibrosis in individuals with NAFLD and to explore the issue of ovarian senescence in experimental liver steatosis in zebrafish. In 244 females and age-matched males with biopsy-proven NAFLD, we assessed anthropometric, biochemical and metabolic features, including menopausal status (self-reported); liver biopsy was scored according to 'The Pathology Committee of the NASH Clinical Research Network'. Young and old male and female zebrafish were fed for 24 weeks with a high-calorie diet. Weekly body mass index (BMI), histopathological examination and quantitative real-time PCR analysis on genes involved in lipid metabolism, inflammation and fibrosis were performed. In the entire cohort, at multivariate logistic regression, male gender [odds ratio (OR): 1.408, 95% confidence interval (95% CI): 0.779-2.542, P=0.25] vs women at reproductive age was not associated with F2-F4 fibrosis, whereas a trend was observed for menopause (OR: 1.752, 95% CI: 0.956-3.208, P=0.06). In women, menopause (OR: 2.717, 95% CI: 1.020-7.237, P=0.04) was independently associated with F2-F4 fibrosis. Similarly, in overfed zebrafish, old female fish with failing ovarian function [as demonstrated by extremely low circulating estradiol levels (1.4±0.1 pg/µl) and prevailing presence of atretic follicles in the ovaries] developed massive steatosis and substantial fibrosis (comparable with that occurring in males), whereas young female fish developed less steatosis and were totally protected from the development of fibrosis. Ovarian senescence significantly increases the risk of fibrosis severity both in humans with NAFLD and in zebrafish with experimental steatosis.
authors.affiliation: Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Turola
authors.affiliation: Division of Gastroenterology, DiBiMIS, University of Palermo, 90128 Palermo, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Petta
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Vanni
authors.affiliation: Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Milosa
authors.affiliation: Department of Pathophysiology and Transplantation, Section Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20122 Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.affiliation: Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy.
authors.forename: Rosina
authors.initials: R
authors.lastname: Critelli
authors.affiliation: Institute of Internal Medicine, School of Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Miele
authors.affiliation: Department of Pathology, University of Modena and Reggio Emilia, 41124 Modena, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Maccio
authors.affiliation: Division of Gastroenterology, DiBiMIS, University of Palermo, 90128 Palermo, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Calvaruso
authors.affiliation: Department of Pathophysiology and Transplantation, Section Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20122 Milano, Italy.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Fracanzani
authors.affiliation: Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Bianchini
authors.affiliation: Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy.
authors.forename: Nazarena
authors.initials: N
authors.lastname: Raos
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bugianesi
authors.affiliation: Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Mercorella
authors.affiliation: Department of Pathology, University of Modena and Reggio Emilia, 41124 Modena, Italy.
authors.forename: Marisa
authors.initials: M
authors.lastname: Di Giovanni
authors.affiliation: Division of Gastroenterology, DiBiMIS, University of Palermo, 90128 Palermo, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Craxì
authors.affiliation: Department of Pathophysiology and Transplantation, Section Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20122 Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.affiliation: Institute of Internal Medicine, School of Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Grieco
authors.affiliation: Division of Gastroenterology, DiBiMIS, University of Palermo, 90128 Palermo, Italy.
authors.forename: Calogero
authors.initials: C
authors.lastname: Cammà
authors.affiliation: Department of Biosciences, University of Milan, 20122 Milan, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Cotelli
authors.affiliation: Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy erica.villa@unimore.it.
authors.forename: Erica
authors.initials: E
authors.lastname: Villa
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000886:Anthropometry; D001706:Biopsy; D015992:Body Mass Index; D016922:Cellular Senescence; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000473:pathology*; D008297:Male; D008593:Menopause; D008875:Middle Aged; D023421:Models, Animal; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology*; D016017:Odds Ratio; D010053:Ovary / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D015027:Zebrafish
keywords: Fibrosis; Menopause; Non-alcoholic fatty liver disease; Ovarian senescence; Zebrafish