Liver sinusoidal endothelial cells (LSECs) protect the liver, acting as the first barrier against insults coming from the sinusoidal blood. LSEC dysfunction is associated with the development of a wide range of liver diseases including alcohol liver disease. Cytochrome P450 2E1 (CYP2E1) is a key enzyme in alcohol and drug metabolism. Induction of CYP2E1 by alcohol generates metabolic products, such as reactive oxygen species (ROS), which cause tissue injury. The study of CYP2E1 in the liver has largely focused on hepatocytes. The presence and function of CYP2E1 in LSECs remains unknown. We recently found that CYP2E1 is expressed in LSECs. This finding is important, since it implies that LSEC-mediated metabolism of alcohol may generate metabolites that impair normal endothelial cell function. The goal of this study is to understand the role of CYP2E1 in LSECs in ethanol-induced liver injury. Dysfunctional LSECs are characterized by loss of fenestrae and decreased nitric oxide (NO) production. NO is a key regulator of intrahepatic vascular tone. NO is also essential for the maintenance of LSEC's fenestrae structure, which allows bi-directional movement of proteins and other substances between blood vessels and hepatocytes. Chronic alcohol consumption decreases endothelial NO synthase (eNOS)-derived NO production. Further, blocking NO production enhances ethanol-induced liver injury, suggesting NO's protective role. The mechanisms by which alcohol consumption diminishes eNOS activity and NO production are unknown. We hypothesize that ethanol induces CYP2E1 expression in LSECs and that induced CYP2E1 in turn decreases eNOS-derived NO production. To test these hypotheses, we will propose the following two aims: 1) Define the role of CYP2E1 in LSEC function in response to ethanol, and 2) Define CYP2E1-dependent regulation of NO production in LSECs in response to ethanol. Given that CYP2E1 metabolizes a wide range of drugs and chemicals besides alcohol, this study will also open the door to reveal LSEC's role in metabolizing those substances, which has most commonly been attributed to hepatocytes.
Alcohol abuse causes liver diseases, whose spectrum includes alcoholic fatty liver, alcoholic hepatitis, fibrosis, cirrhosis and hepatocellular carcinoa in a progressive manner. Early intervention may prevent progression to cirrhosis and hepatocellular carcinoma, but effective treatments are limited due to our incomplete understanding of the molecular and cellular mechanisms of alcohol-induced liver injury. The goal of this proposed research is to understand the mechanisms of alcohol-induced liver injury in which dysfunction of liver sinusoidal endothelial cells, the first barrier of the liver against insults from blood, has a pivotal role.
