Introduction
Cholesterol is a waxy, fat-like substance that is found in the cells of your body and is essential for various physiological functions. It is an important component of cell membranes and plays a crucial role in the production of hormones, vitamin D, and bile acids that aid in the digestion of fats. While cholesterol is necessary for these functions, it can also pose health risks when levels in the blood become too high.
Cholesterol is transported in the bloodstream in the form of lipoproteins, which are combinations of proteins and fats. There are two primary types of lipoproteins that transport cholesterol:
- Low-Density Lipoprotein (LDL): Often referred to as "bad" cholesterol, LDL carries cholesterol from the liver to cells in the body. If there is an excess of LDL in the blood, it can accumulate in the walls of arteries, leading to atherosclerosis (the build-up of plaque) and increasing the risk of heart disease and stroke.
- High-Density Lipoprotein (HDL): HDL is known as "good" cholesterol because it helps remove excess cholesterol from the bloodstream and transport it back to the liver for excretion. Having higher levels of HDL is associated with a lower risk of heart disease.
It's important to maintain a balance between these two types of cholesterol to promote heart health. High levels of LDL cholesterol and low levels of HDL cholesterol are risk factors for cardiovascular diseases. Lifestyle factors such as diet, exercise, and genetics can influence your cholesterol levels. To manage cholesterol levels, many people adopt a heart-healthy lifestyle, including a diet low in saturated and trans fats, regular physical activity, and, in some cases, medication prescribed by a healthcare provider.
Regular monitoring of cholesterol levels through blood tests is essential to assess your risk of heart disease and make informed decisions about your health. Maintaining healthy cholesterol levels is a key component of overall well-being and can help reduce the risk of serious cardiovascular problems.
The Problem
Hypercholesterolemia is a medical condition characterized by high levels of cholesterol in the blood. When cholesterol levels become excessively high, it can lead to several health risks and complications including but not limited to…
- Atherosclerosis: One of the most significant health risks of hypercholesterolemia is the development of atherosclerosis. Atherosclerosis is a condition in which cholesterol and other fatty substances, along with calcium and cellular waste products, build up in the walls of arteries. Over time, this buildup, known as plaque, narrows and hardens the arteries, restricting blood flow. This can lead to various cardiovascular problems.
- Coronary Artery Disease (CAD): CAD occurs when atherosclerosis affects the coronary arteries, which supply oxygen and nutrients to the heart muscle. When these arteries become narrowed or blocked due to plaque buildup, it can result in angina (chest pain) or even heart attacks.
- Stroke: High cholesterol levels can also increase the risk of stroke. If atherosclerosis affects the carotid arteries (the blood vessels that supply the brain), it can lead to the formation of blood clots or plaque fragments that may block blood flow to the brain, causing a stroke.
It's important to note that hypercholesterolemia often doesn't present obvious symptoms, so many people may not be aware of their elevated cholesterol levels until they experience a cardiovascular event or undergo screening tests.
Hypercholesterolemia is a common health condition. In many developed countries, a significant portion of the population has elevated cholesterol levels. It's estimated that over 102 million American adults age 20 or older have total cholesterol levels above 200 mg/dL, which is considered high.
Hypercholesterolemia is a global health concern. It affects people of all ages, ethnic backgrounds, and genders. High cholesterol levels contribute to the global burden of cardiovascular diseases, which are the leading cause of death worldwide.
It's important to note that the prevalence and impact of hypercholesterolemia can vary by region, age group, and other demographic factors.
Current Treatments
Treatment for hypercholesterolemia typically involves lifestyle changes and medications. However, here are some common approaches to treating hypercholesterolemia:
- Lifestyle Changes:
- Dietary Modifications: Reducing saturated and trans fats, cholesterol-rich foods, and increasing fiber intake can help lower cholesterol levels.
- Regular Exercise: Engaging in regular physical activity can raise HDL (good) cholesterol and lower LDL (bad) cholesterol.
- Weight Management: Maintaining a healthy weight can help improve cholesterol profiles.
- Statins:
- Cholesterol Management: Statins are primarily used to reduce levels of low-density lipoprotein (LDL) cholesterol, often referred to as "bad" cholesterol. High levels of LDL cholesterol are a major risk factor for cardiovascular diseases, including heart attacks and strokes.
- How Statins Work: Statins work by inhibiting an enzyme called HMG-CoA reductase, which is involved in the production of cholesterol in the liver. By blocking this enzyme, statins reduce the liver's ability to produce cholesterol, leading to lower LDL cholesterol levels in the bloodstream.
- For all the benefits of statins there are quite a few drawbacks.
- Muscle Pain and Weakness (Myalgia): One of the most commonly reported side effects of statins is muscle pain and weakness. In some cases, this can progress to a more serious condition known as myopathy or rhabdomyolysis, although these severe muscle-related problems are rare.
- Liver Enzyme Elevation: Statins can sometimes lead to an increase in liver enzyme levels in the blood. While this is typically not associated with liver damage, healthcare providers may monitor liver function regularly in patients taking statins.
- Gastrointestinal Symptoms: Some individuals may experience digestive issues, such as nausea, diarrhea, or constipation, while taking statins.
- Cognitive Side Effects: There have been reports of cognitive side effects, such as memory problems or confusion, associated with statin use. However, the evidence for this is mixed, and further research is needed to understand these potential effects fully.
- Increased Blood Sugar Levels: Statins may slightly elevate blood sugar levels in some people, potentially increasing the risk of developing diabetes, especially in individuals with preexisting risk factors for diabetes.
- Varying Affects: Statins produce a variety of effects for different people. Statins are even found to be completely ineffective in some.
- Cost: Statins can be relatively expensive, depending on the specific medication and insurance coverage. Cost considerations may affect an individual's ability to adhere to prescribed therapy.
Our Solution
The Decholesterizer is a two-step circuit that will first detect cholesterol levels and then inhibits the cholesterol production.
- Cholesterol Biosensor, pSRE:
- Cholesterol biosynthesis is regulated by the sterol regulatory element binding proteins (SREBP) system which contains sterol regulatory elements (SRE).
- These SRE elements were transferred into a cytomegalovirus (CMV) promoter creating an engineered pSRE promoter that acts as a cholesterol biosensor.
- Cholesterol Regulator, shRNA:
- The inhibitory part of the Decholesterizer will contain a short hairpin RNA (shRNA) that will knockout squalene monooxygenase (SQLE) to down-regulate cholesterol production.
- Since liver is the primary organ that is involved in the synthesis of cholesterol, we have selected to perform our studies in human liver cells. The liver HepG2 cells were modified with a plasmid to detect changes in cholesterol levels and in parallel, with a siRNA to inhibit cholesterol biosynthesis.
- The Decholesterizer would provide an alternative treatment to hypercholesterolemia. This treatment would be tailored to each patient to effectively regulate cholesterol levels while hopefully minimizing, if not eliminating, the major side effects of statins.