| SES # | TOPICS | LECTURE SUMMARIES |
|---|---|---|
| 1 | Introduction | Introduction of course, instructor, students. How to access scientific literature and how to make a literature search. |
| 2 | Inborn errors of cholesterol biosynthesis | Cholesterol is a major constituent of all our membranes and serves as a substrate for the biosynthesis of steroid hormones and bile acids. Therefore, it is not surprising that inborn errors of cholesterol synthesis have drastic consequences for the affected individuals. Although clinically described in 1964, it was only in 1994 that Smith-Lemli-Opitz Syndrome was identified as a disorder of cholesterol biosynthesis. This week, we will discuss a mouse model for Smith-Lemli-Opitz Syndrome and one probable mechanism as to how cholesterol depletion may cause some of the developmental defects observed in this disorder. |
| 3 | LDL receptor endocytosis, familial hypercholesterolemia | In 1985, Michael S. Brown and Joseph L. Goldstein received the Nobel Prize in Physiology or Medicine for discovering how our cells uptake cholesterol from circulating blood by identifying the low-density lipoprotein (LDL) receptor pathway. In addition, they determined how a defect in this pathway can lead to atherosclerosis as in the genetic disorder familial hypercholesterolemia (FH). This week, we will discuss one of the earliest papers from Brown and Goldstein showing the lipoprotein binding defect in FH patients and how this defect alters the de novo synthesis of cholesterol and a mouse model with a targeted deletion of the LDL receptors. |
| 4 | Cholesterol sensing in the cells | In our cells, the supply of cholesterol is coordinated via transcriptional and posttranscriptional mechanisms that control genes and gene products required for cholesterol synthesis or uptake. This week we will discuss the discovery of one of the sensors involved in control of these mechanisms and the consequences of overexpressing this protein in vivo. |
| 5 | Atherosclerosis | Atherosclerosis is the principal cause of heart disease and stroke, the number 1 and number 3 killers in western industrialized societies, and accounts for 50% of all deaths. Atherosclerosis is a progressive disease caused by plaque buildup in the arterial wall. The plaque is formed by cholesterol deposits brought in by plasma lipoproteins. This week, we will discuss mouse models of atherosclerosis to gain insight into the mechanism of plaque formation. We will look at what causes the retention of cholesterol-carrying plasma lipoproteins in the arterial wall and involvement of a protein kinase in plaque formation. |
| 6 | Statins | Statins are the most prescribed drug on the market for lowering LDL cholesterol. This week, we will discuss the original article by Akira Endo reporting his discovery of the first statin. We will also look at the structural mechanism of statin inhibition of HMG-CoA reductase. |
| 7 | Cholesterol absorption inhibitors | The new drug ezetimibe has a unique mechanism for lowering cholesterol: it inhibits the intestinal absorption of dietary and biliary cholesterol. This week, we will discuss how ezetimibe and its target were identified. |
| 8 | Atherosclerosis and heart attack, current treatments | This week we will take a field trip to Beth-Israel Deaconess Medical Center to meet a cardiologist. |
| 9 | ABCA1, Tangier disease | The high-density lipoprotein (HDL) is known as 'good cholesterol', because HDL levels in blood are inversely correlated with development of heart disease. Tangier Disease is a rare genetic disorder that is characterized by severe deficiency of high-density lipoprotein (HDL) in blood and premature atherosclerosis. The cause of Tangier Disease was found independently by 4 laboratories as a genetic defect in the ABCA1 gene encoding an ATP-binding cassette transporter. This week, we will look at one of the papers that identified ABCA1 gene as the causative agent in Tangier Disease. We will also discuss a mouse model with a targeted deletion of ABCA1 gene and address why HDL is 'good'. |
| 10 | Increasing HDL, fibrates, diet | Fibrates are commonly used drugs that raise HDL levels in blood. They bind and activate a specific nuclear receptor, called peroxisome proliferator-activated receptor-α (PPAR-α). PPAR-α activates a wide range of genes involved in fatty acid, triglyceride, and cholesterol metabolism and also in lipoprotein formation and remodeling. This week, we will discuss one plausible mechanism by which fibrates might be exerting their favorable effects on HDL levels i.e., by modulating the levels of an HDL receptor. We will also discuss monozygotic twin studies to shed a light on whether it is nature or 'nurture' that defines one's plasma lipoprotein response to dietary fat change. |
| 11 | Cholesterol in the brain, Alzheimer's disease | The synaptic contact formation is critical for brain development and for long-term plasticity of the central nervous system. A soluble factor secreted by the glial cells was suggested to promote synapse formation. This week, we will take a look at one of the potential roles of cholesterol in synaptogenesis. In addition, we will discuss potential involvement of dietary cholesterol in development for Alzheimer's disease in a mouse model. |
| 12 | Future of drug therapies | Most of the drugs we use today were discovered without the knowledge of specific mechanisms of action and targets. To achieve safer and more effective drugs with fewer side effects, target identification will be essential. This week, we will discuss use of yeast as a tool to identify targets of some drugs already in use. In addition, we will look at the effects of combination therapy to achieve more effective therapies. |
| 13 | Discussion of assignment 2 | During this session we will discuss the take-home lessons of the course and discuss assignment 2. |