Hormonal control of NASH development and progression

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Abstract/Summary Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of pathologies ranging from simple steatosis to non-alcoholic steatohepatitis (NASH – steatosis, hepatocyte ballooning and inflammation, with or without fibrosis). Highly prevalent in obese and diabetic patients, NASH is an independent risk factor for cardiovascular disease, cirrhosis, and hepatocellular carcinoma, devastating diseases that are more prevalent in veterans than in the general population. Women of reproductive age have lower rates of NASH; however, this protection is lost after menopause when NASH rates equal or exceed those for men. Both clinical and experimental data indicate that estrogen plays a major role in protecting women against NASH. Moreover, the protective effects of estrogen may also extend to men via tissue-dependent aromatization of androgens to estrogens. Despite this knowledge, the precise tissue-specific mechanisms for estrogen-mediated protection have not been directly investigated. This proposal will focus on the interrelationship between estrogen and growth hormone (GH), specifically at the level of the hepatocyte, where published literature and preliminary data generated by our group have led to the HYPOTHESIS that the estrogen receptor, ER, as well as the GH receptor (GHR), are required to slow NASH development in part by sustaining hepatocyte Stat5b activity. Studies will compare male and female mice with adult-onset, hepatocyte-specific, knockdown of the estrogen receptor, ER or GHR alone, or in combination to: SA1 Determine the role of ER in hepatocyte Stat5b action and its impact on hepatic function and physiology in the presence and absence of GHR-mediated signaling; SA2 Determine if hepatocyte ER protects against diet- induced NASH, in the presence and absence of GHR; SA3 Determine if hepatocyte ER and/or GHR play a role in tamoxifen (TAM) induced NASH progression. Endpoint analysis includes assessment of 1) GH-axis function, whole body metabolism, liver lipid content and pathology, 2) Hepatic response to acute GH challenge (western blot analysis of downstream intracellular signals and 3) Hepatic cell-type specific gene expression using single nuclei RNA-Seq (snRNA-Seq), a technique that provides important information on the potential crosstalk between cell types within the liver, critical for NASH development. The outcomes of this project will generate new mechanistic insights to identify future drug targets to prevent NASH progression in both male and female veterans.