Cholesterol

Introduction – Cholesterol

Cholesterol is a type of fat that is essential for many bodily functions. It is found in every cell of the body and plays a vital role in the production of hormones, vitamin D, and bile acids that help digest fat. Cholesterol is also important for the structure and function of cell membranes.

Cholesterol is produced by the liver and is also obtained through the diet. It is transported in the bloodstream by lipoproteins, which are made up of cholesterol and proteins. There are two types of lipoproteins that carry cholesterol in the blood: low-density lipoproteins (LDL) and high-density lipoproteins (HDL). LDL is sometimes referred to as “bad” cholesterol because it can contribute to the buildup of plaque in the arteries, while HDL is often referred to as “good” cholesterol because it helps remove excess cholesterol from the bloodstream.

Overview

•  Function
  • component of cell membrane
  • precursor for hormone synthesis
    • steroids
    • vitamin D
  • precursor for bile acid synthesis
    • means of excretion
      • >95% of bile acids are reabsorbed
    • ↑ in bile acid production used as a means to treat hypercholesterolemia
      • cholestyramine
        • resin that binds bile acids in the GI tract and prevents reabsorption
        • increases serum cholesterol usage in bile acid production
        • ↑ regulates LDL receptor
• Sources
  • dietary intake
    • circulating serum LDL
      • uptake via endocytosis of LDL:LDL receptor complex
    • circulating serum HDL
      • transfer of cholesterol from HDL to hepatocyte via scavenger receptor (SR-B1)
        • high levels of this receptor in
          • hepatocytes
          • steroid producing tissues
  • de novo synthesis
    • occurs in hepatocytes
    • HMG-CoA reductase is rate limiting enzyme
      • inhibited by statins, glucagon, cholesterol
      • activated by insulin
• Regulation
  • ↑ in intrahepatic [cholesterol]
    • ↓ expression of
      • HMG-CoA reductase
        • ↓ de novo cholesterol synthesis
      • LDL-receptor
        • ↓ in cholesterol-containing LDL uptake from serum
      • scavenger receptor (SR-B1)
        • ↓ cholesterol uptake from HDL
• Transport
  • cholesterol is fat-soluble
    • ↑ transport by synthesis of a cholesteryl ester
      • dissolves into center of HDL
      • catalyzed by lecithin-cholesterol acyltransferase (LCAT)
        • enzyme in serum
        • activated by apoA-1 of HDL
  • see Apolipoproteins topic 
• Pathology
  • familial hypercholesterolemia 
    • defective LDL receptor
    • AD 
    • presentation
      • cholesterol deposition in skin
        • xanthelasma
          • in eyelid
        • tendon xanthomas
          • in skin above tendons
      • ↑ risk for coronary heart disease
  • atherosclerosis
    • risk factors (causes of endothelial cell damage)
      • smoking
      • ↑ LDL in serum
      • homocystinemia
      • diabetes
    • protective factors
      • antioxidants
        • vitamin E
          • protects LDL from oxidation
    • process
      • injury to endothelial cells of blood vessels
      • an inflammatory state is induced
        • T-cell activation
        • similar to a granuloma
      • cholesterol in the blood deposits in blood vessels
      • LDL oxidized and phagocytosed by macrophages
        • can become full of cholesterol
          • foam cells
      • fatty streak formed
      • fatty streak enlarges
      • fibrous cap formed
        • smooth muscle and endothelial cells migrate over the fatty streak
        • underlying tissue forms necrotic core
      • cap at risk of rupturing
• exposes underlying endothelium and causes thrombosis

Symptoms

• Heart disease: Symptoms of heart disease may include chest pain or discomfort, shortness of breath, nausea, lightheadedness, and discomfort in the arms, back, neck, jaw, or stomach. In some cases, heart disease may cause no symptoms at all.
• Stroke: Symptoms of stroke may include sudden numbness or weakness in the face, arm, or leg (especially on one side of the body), confusion, trouble speaking or understanding speech, difficulty seeing in one or both eyes, trouble walking, dizziness, and severe headache.
• Peripheral artery disease (PAD): Symptoms of PAD may include leg pain, cramping, numbness, weakness, or coldness in the legs or feet, especially during exercise or while walking.

Studies

• High levels of LDL cholesterol are a major risk factor for heart disease and stroke. According to the American Heart Association, high LDL cholesterol levels can cause the buildup of plaque in the arteries, which can lead to atherosclerosis, a condition in which the arteries become narrowed and hardened. This can increase the risk of heart disease and stroke.
• Low levels of HDL cholesterol have also been linked to an increased risk of heart disease. HDL cholesterol helps remove excess cholesterol from the bloodstream, so low levels may lead to the buildup of plaque in the arteries.
• Lifestyle factors such as diet, exercise, and smoking can affect cholesterol levels. For example, a diet high in saturated and trans fats can increase LDL cholesterol levels, while regular exercise can increase HDL cholesterol levels.
• Statin medications are commonly used to lower cholesterol levels and reduce the risk of heart disease. Statins work by blocking an enzyme in the liver that produces cholesterol. Studies have shown that statins can reduce LDL cholesterol levels by 20-60%, depending on the dose and the individual.
• Other medications, such as bile acid sequestrants and PCSK9 inhibitors, can also be used to lower cholesterol levels.

Treatment

• Lifestyle changes: Making healthy lifestyle changes is often the first line of treatment for high cholesterol. This may include adopting a healthy diet low in saturated and trans fats, increasing physical activity, quitting smoking, and achieving and maintaining a healthy weight.
• Medications: Cholesterol-lowering medications such as statins, bile acid sequestrants, and PCSK9 inhibitors can be prescribed to lower cholesterol levels. These medications work by blocking the production of cholesterol in the liver or by increasing the removal of cholesterol from the bloodstream. The choice of medication and dose depends on the individual’s cholesterol levels and other health factors.
• Combination therapy: In some cases, a combination of lifestyle changes and medication may be necessary to effectively lower cholesterol levels.

Complications

• Heart disease: Atherosclerosis in the coronary arteries can lead to heart disease, which can cause chest pain, heart attack, and heart failure.
• Stroke: Atherosclerosis in the arteries that supply blood to the brain can lead to stroke, which can cause brain damage or death.
• Peripheral artery disease (PAD): Atherosclerosis in the arteries of the legs and feet can cause PAD, which can cause leg pain, cramping, and difficulty walking.
• Aortic aneurysm: Atherosclerosis in the aorta, the largest artery in the body, can cause aortic aneurysm, a bulging or weakening of the aortic wall that can lead to life-threatening rupture or dissection.
• Kidney disease: Atherosclerosis in the renal arteries can lead to kidney disease, which can cause decreased kidney function and, in severe cases, kidney failure.
• Erectile dysfunction: Atherosclerosis in the arteries that supply blood to the penis can lead to erectile dysfunction.

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