Role of obesity and estrogen deficiency in non‑alcoholic fatty liver disease: Insights from a mouse model.

Abstract

The prevalence of non‑alcoholic fatty liver disease (NAFLD) increases in post‑menopausal women, driven by obesity and metabolic syndrome (MS). However, the pathogenesis of this interaction remains poorly understood. The present study investigated the interplay between obesity, menopause and NAFLD in a C57BL6/J mouse model of diet‑induced obesity. The study included male and female animals, in which a subgroup of females underwent ovariectomy to simulate menopause. Mice were fed a high‑fat diet for 6 months which resulted in them becoming overweight, and developing hyperglycemia and insulin resistance. The present study analyzed liver histology, inflammatory markers and hepatic lipid profiles. All obese animals showed liver steatosis, hepatocyte ballooning and fibrosis. Sex‑related differences were observed, including: i) Obese male mice developed increased expression of inflammatory markers and altered lipid profile; ii) obese female mice exhibited less severe steatosis, hepatic inflammation and lipotoxicity, and iii) ovariectomized obese female mice exhibited exacerbated hepatic lipotoxicity and tissue damage. Ovariectomized obese female mice also had reduced triacylglycerol and cholesteryl ester levels, but increased levels of toxic intermediaries, such as free fatty acids, diacylglycerols and free cholesterol, elevated expression of NF‑κB in the liver and increased levels of serum transaminases, indicating liver damage. These findings suggested that estrogen may protect against NAFLD progression by regulating lipid droplet formation, especially in the context of insulin resistance. More studies in the field are clearly needed to achieve a complete understanding of these pathways, which may serve to improve current therapies.