Regulation of Hepatic P450s by Anti-Cholesterol Drugs

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Cardiovascular diseases, which include coronary artery disease and stroke, are the leading causes of morbidity and mortality in the United States. Elevated levels of LDL cholesterol are a major risk factor for coronary artery disease, and more than 30% of American adults and 7% of adolescents have high LDL cholesterol levels. There is a log-linear relationship between blood cholesterol level and mortality due to coronary artery disease, which indicates the benefit of cholesterol reduction regardless of the starting level. The liver plays a dominant role in cholesterol metabolism, so many pharmacological approaches to lower cholesterol target the liver. The “statins” have proven effective at reducing cholesterol levels and mortality due to coronary artery disease, and they are therefore among the most widely used drugs in the United States. However, statins also produce adverse effects and undergo drug-drug interactions. Our goal is to understand the spectrum of mechanisms by which statins and other drugs that interfere with cholesterol metabolism regulate hepatic processes. This project focuses on a non-therapeutic consequence of cholesterol synthesis inhibition that involves an interaction with the constitutive androstane receptor (CAR), a xenobiotic-sensing regulator of drug, glucose, and lipid metabolism. This interaction does not occur in rodent hepatocytes, emphasizing the need to study the process in human hepatic systems. The hypothesis of this project is that inhibition of cholesterol biosynthesis suppresses CAR activation and target gene expression in human hepatocytes and that this effect is mediated through an inhibitory interaction between CAR and sterol regulatory element binding factor 2 (SREBP2). The specific aims are to (1) define the impact of cholesterol synthesis inhibition on CAR target gene expression in human hepatocytes in vitro and in vivo and (2) define the mechanism by which cholesterol synthesis inhibition regulates CAR target gene expression in human hepatic cells. To investigate the impact of cholesterol synthesis inhibition on CAR-regulated gene expression in a manner that is directly relevant to humans, the study emphasizes the use of human hepatocytes, both in primary culture and in a mouse model. The mechanistic studies consider the complexity of different human CAR isoforms; evaluate the impact of cholesterol synthesis inhibition on CAR expression, activation, and recruitment to the promoters of target genes; and feature determining how an interaction between CAR and SREBP2 could underlie the impact of cholesterol synthesis inhibition on CAR activity. The findings of this study will provide new insight into the fundamental mechanisms by which drugs that inhibit cholesterol biosynthesis can affect human hepatocellular physiology in a manner that alters xenobiotic-sensing receptor-sensitive processes. Because these effects emanate from inhibition of the drug's intended target, they are not easily dissociated from the drug's therapeutic effects. Such effects are potentially relevant to understanding inter- individual differences in metabolism as well as the origin of adverse drug effects.