Molecular mechanisms by which citrus flavonoids regulate cholesterol transport processes in the liver [abstract]

Faculty Mentor: Lené Holland, Medical Pharmacology and PhysiologyAbstract only availableThe American Heart Association estimates that cardiovascular disease will claim the lives of nearly two and a half million Americans in 2006. To combat high cholesterol, one of the most common causes of cardiovascular disease, researchers have been searching for new and innovative ways to lower cholesterol. Recently, flavonoids isolated from citrus fruits have been identified for their keen ability to reduce low-density lipoprotein (LDL) levels in plasma. This observation raises the question of how flavonoids interact with cholesterol metabolism in the liver to produce these effects. It is known that LDL is taken into liver cells via the low-density lipoprotein receptor (LDLR) and is subsequently broken down into cellular cholesterol and triglycerides. The cholesterol can then be reutilized within the cell, excreted as bile, or processed by the microsomal triglyceride transport protein (MTTP) to be returned to the plasma as very-low density lipoprotein. LDLR and MTTP work together to regulate cholesterol levels in hepatocytes. Since both of these genes are controlled by the transcription factor, sterol regulatory element-binding protein (SREBP), we have begun to explore the possibility that flavonoids actually operate through SREBP. To address this hypothesis, we will obtain more accurate measures of LDLR and MTTP mRNA levels through mRNA hybridization and quantitative polymerase chain reaction (PCR) methods. While the hybridizations verify the quality of our PCR products, the quantification using real-time PCR provides a more efficient way to evaluate the changes in mRNA expression. These data will permit further investigation of the specific role of SREBP in the transcriptional regulation of MTTP and LDLR by citrus flavonoids. Ultimately, we will gain invaluable information on decreasing the risk of cardiovascular disease through cholesterol reductio

Regulation of cholesterol transport processes in the liver by dietary citrus flavonoids [abstract]

Abstract only availableOver the past few years, the importance of diet management and moderation has become a focal point of everyday life. Obesity, high blood pressure, diabetes, and high blood cholesterol can all result from poor nutrition decisions. High plasma levels of low-density lipoprotein (LDL), the particle which contains cholesterol, are of particular interest as this condition has been classified as one of the most prevalent risk factors for heart disease. Individuals affected by high levels of LDL are commonly encouraged to maintain a healthy diet and exercise routine while also receiving medication to expedite the cholesterol reduction. Although several treatment options for high cholesterol have come into common use in recent years, there are always continuing efforts to develop more effective therapies. Recent research on natural food constituents has suggested that citrus flavonoids, found in oranges, tangerines, and grapefruits, may reduce the amount of LDL in the blood. The process of cholesterol metabolism takes place primarily in the liver and, thereby, it is appropriate to analyze the effect of flavonoid treatment on hepatocytes. The low-density lipoprotein receptor (LDLR) and the microsomal triglyceride transfer protein (MTTP) control the amount of LDL circulating in the blood. The genes coding for these two proteins are believed to be regulated by the transcriptional regulatory protein, sterol regulatory element binding protein. Citrus flavonoids induce the expression of LDLR mRNA and suppress that for MTTP. This action will increase the amount of LDLR protein and decrease the amount of MTTP protein in liver cells, thus resulting in lower plasma levels of LDL. To determine the roles of LDLR and MTTP mRNA expression in the mechanism of flavonoid activity in the liver, we have used quantitative real-time polymerase chain reactions in dose response studies to determine the most effective concentration of citrus flavonoid treatment.Life Sciences Undergraduate Research Opportunity Progra