Understanding the relationship between sex and non-alcoholic fatty liver disease
Miller, Colette Nicole
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The female sex has an innate protection from many metabolic diseases including non-alcoholic fatty liver disease (NAFLD) most commonly attributed to 17β-estradiol (E2). The goal of this dissertation is to provide further evidence behind the relationship of sex and NAFLD risk, and to develop potential explanations for this protection. Childhood risk of NALFD can be influenced by maternal obesity and the pre-natal environment including hormones. To determine if early metabolic sex differences can be found, livers from post-natal day 21 mice from lean and obese dams were assayed. While both sexes responded similarly to many of the selected measurements, sex differences in genes related to insulin signaling (GLUT 4 and IRS1) and the endoplasmic reticulum stress response were detected. In an acute hepatic injury model, male and female rats were fed a high fat diet for 72 hours. In that time period a large sex difference emerged in expression of genes related to apoptosis, cell repair, and remodeling in the liver, such that females appeared better able to adapt to this high fat diet. This is consistent with other acute injury models that show that E2 induces a pro-inflammatory state that is necessary for survival during acute stress and injury. Lastly, to investigate the efficacy of phytoestrogens to prevent ovariectomy-induced NAFLD, a phytochemical blend of resveratrol, genistein, and quercetin was fed to ovariectomized rats. Due to the lipolytic and anti-adipogenic properties of the selected compounds, an increase in lipid mobilization and hepatic fat accumulation was measured. Despite this, the phytochemical blend reduced apoptotic and fibrogenic gene expression. Furthermore, the high-dose blend reversed ovariectomy-induced increases in serum alanine aminotransferase. Lastly, taking into account the entirety of this work, we have developed three hypotheses by which the female sex may be protected from NAFLD: (1) an inherent difference in endoplasmic reticulum stress and insulin sensitivity at birth that is most likely epigenetically regulated, (2) a rapid and heightened response to acute hepatic injuries including short exposures to high fat diets, and (3) the anti-inflammatory and cytoprotective effects of estradiol and its mimetics.