Chronic ethyl alcohol (EtOH) consumption causes fatty liver (steatosis), but does not usually result in cirrhosis unless fatty liver hepatitis (steatohepatitis) develops. Thus, the transition from steatosis to steatohepatitis may be a rate-limiting step in the evolution of cirrhosis. Factors that induce TNFalpha or enhance hepatocyte vulnerability to its lethality potentiate progression to steatohepatitis. However, the mechanisms involved are not understood. Obesity is a risk factor for EtOH-related cirrhosis and, even in non-drinkers, is often associated with fatty liver. There are similarities between genetically obese, ob/ob mice with fatty livers and mice EtOH-induced fatty livers-both develop severe liver damage when challenged by small amounts of endotoxin or transient hypoxia. The investigator's preliminary data suggest that obesity actually potentiates the hepatotoxicity of EtOH because, unlike lean mice, ob/ob mice develop steatohepatitis when drinking EtOH chronically. Thus, the ob/ob mouse is a novel small animal model that can be used to characterize mechanisms that mediate the transition from steatosis to steatohepatitis. The purpose of this project is to use this model to evaluate the individual, and combined, effects of obesity and Et-OH-exposure on hepatic mitochondria. Mitochondria regulate cell viability by controlling ATP production and the release of noxious substances, including reactive oxygen species and pro-apoptotic factors. The mitochondrial uncoupling protein, UCP2, limits both ATP and ROS production during mitochondrial respiration and, thus, might modulate susceptibility to necrosis and/or apoptosis. The investigators have new evidence that obesity, and other factors that potentiate EtOH-related hepatotoxicity, up-regulate the expression of UCP2 in hepatocytes. This project will evaluate the HYPOTHESIS that hepatocytes that have already adapted to obesity by up-regulating UCP2 are particularly prone to develop lethal mitochondrial dysfunction when exposed to EtOH. Pair feeding studies in ob/ob and learn mice and experiments in cultured hepatocytes will address three Specific Aims: 1) to characterize the effects of EtOH, obesity, and EtOH + obesity on hepatic UCP2 expression, vital mitochondrial parameters (e.g., glutathione levels, cytochrome c release, ROS and ATP production), and liver damage; 2) to determine if UCP2 induction potentiates mitochondrial membrane depolarization by EtOH or other factors (e.g., TNFalpha) that promote EtOH-hepatotoxicity; and 3) to determine if increased ROS production induces UCP2 and, thus, if inhibiting ROS by antioxidant therapy will prevent UCP2 induction, mitochondrial dysfunction, and liver damage.
| Li, Yin-Xiong; Yang, Hai-Tao; Zdanowicz, Marzena et al. (2007) Fetal alcohol exposure impairs Hedgehog cholesterol modification and signaling. Lab Invest 87:231-40 |
| Sicklick, Jason K; Li, Yin-Xiong; Melhem, Alaa et al. (2006) Hedgehog signaling maintains resident hepatic progenitors throughout life. Am J Physiol Gastrointest Liver Physiol 290:G859-70 |
| Suzuki, Ayako; McCall, Shannon; Choi, Steve S et al. (2006) Interleukin-15 increases hepatic regenerative activity. J Hepatol 45:410-8 |
| Choi, Steve S; Sicklick, Jason K; Ma, Qi et al. (2006) Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice. Hepatology 44:1267-77 |
| Sicklick, Jason K; Choi, Steve S; Bustamante, Marcia et al. (2006) Evidence for epithelial-mesenchymal transitions in adult liver cells. Am J Physiol Gastrointest Liver Physiol 291:G575-83 |
| Sicklick, Jason K; Li, Yin-Xiong; Jayaraman, Aruna et al. (2006) Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis 27:748-57 |
| Sicklick, Jason K; Li, Yin-Xiong; Choi, Steve S et al. (2005) Role for hedgehog signaling in hepatic stellate cell activation and viability. Lab Invest 85:1368-80 |
| Gao, Daqing; Wei, Chiming; Chen, Lei et al. (2004) Oxidative DNA damage and DNA repair enzyme expression are inversely related in murine models of fatty liver disease. Am J Physiol Gastrointest Liver Physiol 287:G1070-7 |
| Diehl, Anna Mae (2004) Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease. Clin Liver Dis 8:619-38, x |
| Yang, Shiqi; Koteish, Ayman; Lin, Huizhi et al. (2004) Oval cells compensate for damage and replicative senescence of mature hepatocytes in mice with fatty liver disease. Hepatology 39:403-11 |
Showing the most recent 10 out of 13 publications
