BIOENERGETICS AND ALCOHOLIC LIVER DISEASE PATHOGENESIS

Johns Hopkins University, Baltimore MD

Investigators

Linked publications & trials

Abstract

DESCRIPTION: (Adapted from the Investigator's Abstract): 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.