Roles of estrogen hormones and estrogen receptors on regulation of liver and liver cancer metabolism

Liver is one of the most essential organs involved in the regulation of energy homeostasis. Hepatic steatosis, a major manifestation of metabolic syndrome, is associated with imbalance between lipid formation and breakdown and glucose production and catabolism. Although the most common risk factors of hepatocellular carcinoma (HCC) are hepatic virus infection and alcohol, a rapid increase in obesity has become a prime cause of HCC, outweighing HCC with virus- or alcohol- related etiology. Estrogens affect both cell metabolism and proliferation. Both nuclear estrogen receptors (ERs), ER-a and ER-ß, are expressed in the liver. How estrogen hormones regulate liver homeostasis and which receptors play the fundamental role in the metabolic process are not clear. Moreover, whether estrogen hormones and ERs are protective or detrimental in HCC is under debate, and whether estrogens can alter HCC metabolism and interfere with leptin-induced HCC is not known. The goal of my dissertation is to further elucidate the roles of estrogens and ERs in normal liver metabolism as well as HCC metabolism and proliferation using both in vivo and in vitro models. Thus, I hypothesize that 1) exogenous estrogen replacement reverses liver metabolic alteration in estrogen-depleted mice mainly through ER-a receptor; 2) estrogens inhibit leptin-induced HepG2 cell proliferation mainly through ER-ß activation and alter HepG2 metabolism mainly through ER-a activation. In this dissertation, previous studies on the functions of estrogen and estrogen receptors in liver and liver cancer are discussed in Chapter 1. Studies using ovariectomized mouse model with hormone-replacement was applied to determine the role of estrogens and estrogen receptors in mouse liver metabolism are discussed in Chapter 2. Human cancer cell line HepG2 was treated with different concentrations of estrogen and estrogen receptor agonists as well as estrogen receptor siRNA to determine the role of estrogen and estrogen receptors on HepG2 cancer cell proliferation, apoptosis and leptin signal pathway in Chapter 3. High performance liquid chromatography (HPLC) was used to determine the role of estrogen and estrogen receptors on HepG2 cancer cell gene expression and metabolic profiles in Chapter 4. In Chapter Five, I conclude the finding of my current studies and give perspectives for future research directions of estrogen hormones and estrogen receptors in the regulation of liver and liver cancer metabolism.