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 severity of liver fibrosis in patients 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-calories diet. Weekly BMI, histopathological examination, quantitative RT-PCR on genes involved in lipid metabolism, inflammation and fibrosis were performed. In the entire cohort, at multivariate logistic regression, male gender (OR: 1.408, CI: 0.779-2.542, p=0.25) vs. women at reproductive age was not associated with F2-F4 fibrosis, while 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) while young female fish developed less steatosis and were totally protected from development of fibrosis. Ovarian senescence significantly increases the risk of fibrosis severity both in humans with NAFLD and in zebrafish with experimental steatosis.