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Dis Model Mech. 2015 Sep;8(9):1037-46. doi: 10.1242/dmm.019950. Epub 2015 Jul 16.

Ovarian senescence increases liver fibrosis in humans and zebrafish with steatosis.

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Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy.
Division of Gastroenterology, DiBiMIS, University of Palermo, 90128 Palermo, Italy.
Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
Department of Pathophysiology and Transplantation, Section Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20122 Milano, Italy.
Institute of Internal Medicine, School of Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy.
Department of Pathology, University of Modena and Reggio Emilia, 41124 Modena, Italy.
Department of Biosciences, University of Milan, 20122 Milan, Italy.
Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy


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.


Fibrosis; Menopause; Non-alcoholic fatty liver disease; Ovarian senescence; Zebrafish

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