21.1: Introduction to Lipoprotein and Apolipoproteins
By the end of this section, you should be able to:
- 21.1.1 Discuss fat metabolism and the role of lipoproteins and apolipoproteins in the body.
- 21.1.2 Discuss the role of lipids as a risk factor for coronary artery disease.
Understanding Lipids
Triglycerides are the main dietary source of fat. They are composed of three long fatty acid chains attached to a glycerol backbone, as depicted in Figure 21.2. The major sterol in the body is cholesterol. Cholesterol is important for the structure of cell membranes and for the production of hormones, bile acids, and vitamin D.
Lipid Metabolism
Fats from the diet are emulsified by bile acids, which are made in the liver and secreted by the gallbladder when food is consumed. The emulsified fats are absorbed in the small intestine and carried via chylomicrons to the tissues. Chylomicrons interact with an enzyme called lipoprotein lipase on muscle and adipose tissue, thereby facilitating the release of free fatty acids from the triglycerides. The free fatty acids can be burned by the tissues for energy or stored as fat. The remnants of chylomicrons that are left over after fatty acid delivery return to the liver. Apolipoproteins A, B, C, and E are all involved in different aspects of this pathway.
The liver also synthesizes cholesterol and triglycerides. Cholesterol is synthesized via an enzyme called HMG CoA reductase , which is a key drug target in lipid-lowering therapy. The liver then packages cholesterol and triglycerides into VLDL particles, which travel to muscle and adipose tissue. Lipoprotein lipase breaks down VLDL particles to release free fatty acids from triglycerides for energy or storage. The remnants left over from the VLDL particles are called intermediate-density lipoproteins, which can be disposed of by the liver or further broken down by lipases to form LDL particles. LDL receptors in the liver interact with LDL-cholesterol to engulf it via endocytosis and dispose of it, effectively removing it from circulation. A protein called PCSK9 interacts with the LDL receptors, leading to their degradation; this is another important drug target in lipid-lowering therapy. HDL-cholesterol also assists in removing cholesterol from the circulation.
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Ketogenic Diet
The ketogenic diet , often called “keto,” was originally used to help children suffering from frequent seizures. However, it has recently become a popular diet for those seeking weight loss. The diet consists of very low amounts of carbohydrates and higher amounts of fat. When very low amounts of carbohydrates are consumed, the body uses ketone bodies, made from fats, as the major fuel instead of glucose. Although this diet can lead to rapid weight loss, it can be very difficult to sustain. A typical 2000-calorie ketogenic diet would limit carbohydrates to 20–50 g per day (Masood et al., 2022). A single apple could satisfy the entire daily intake of carbohydrate for a ketogenic diet. The keto diet also may be associated with increased lipid levels and cardiovascular disease.
Lipids and Coronary Artery Disease
Cholesterol has a central role in the development of coronary artery disease (CAD). CAD is characterized by plaque buildup within the coronary arteries, which can occlude blood flow to the heart muscle. The development of CAD starts with cholesterol and triglycerides, which can be deposited onto the inner walls of arteries. Cells from the immune system called macrophages engulf the cholesterol, forming foam cells and fatty streaks within the arterial wall. Over time, cells and cellular debris build up on the fatty streaks, and a fibrous cap forms to create plaques that can narrow the artery and obstruct blood flow. Rupture of the fibrous plaque can cause a thrombus, or blood clot, to form at the site, possibly resulting in complete arterial occlusion and acute myocardial infarction.
Link to Learning
Cholesterol and Coronary Artery Disease
This interactive slide presentation from the American Heart Association introduces the role of cholesterol in the pathophysiology of CAD.
Because of this pathophysiology, hypercholesterolemia due to elevated LDL-cholesterol is an independent risk factor for heart disease. Lipid-lowering therapy that targets LDL-cholesterol is used to decrease the risk for CAD. The optimal target levels for LDL-cholesterol and specific treatment strategies recommended in national guidelines have changed over the last 15 years and continue to evolve; however, the role of LDL-cholesterol as an independent risk factor has not changed.
Although triglycerides have been implicated in the development of atherosclerosis, treatment has not resulted in positive cardiovascular outcomes. Therefore, hypertriglyceridemia is generally not treated unless it is very severe (greater than 500 mg/dL), which can put the individual at risk for pancreatitis.
HDL-cholesterol actually has a protective role against cardiovascular disease, and higher levels (Table 21.1) are considered beneficial.
Link to Learning
This video from JAMA Network gives a quick overview of cholesterol management according to the 2018 American College of Cardiology/American Heart Association guidelines. It provides some context on the changes from previous management recommendations.
In general, lifestyle changes are considered the first-line therapy to treat dyslipidemia and prevent CAD. Many therapeutic drugs are also available. These drugs are listed in Table 21.2 and are the focus of the remainder of the chapter.
| Primary Target to Decrease* | Drug Classes or Drugs | Drug Mechanism |
|---|---|---|
| LDL-cholesterol | Ezetimibe | Decreases cholesterol absorption |
|
Statins
Bempedoic acid |
Decrease cholesterol synthesis | |
|
PCSK9 inhibitors
Inclisiran |
Increase cholesterol removal | |
| Niacin | Multiple actions; not well understood | |
| Triglycerides | Fibrates | Stimulate triglyceride breakdown |
| Niacin | Multiple actions; not well understood | |
|
Omega-3 fatty acids
Icosapent ethyl |
Thought to reduce hepatic production of VLDL | |
| Bile acid sequestrants | Divert cholesterol for bile acid production |
Clinical Tip
Diet
A heart-healthy diet can help reduce cardiovascular risk and is the first-line therapy for cardiovascular risk reduction and hyperlipidemia.
Clients should eat:
- Vegetables
- Whole grains
- Legumes
- Healthy protein sources
- Nontropical vegetable oils
Clients should limit intake of:
- Sweets
- Sugar-sweetened beverages
- Red meats
- Saturated fats and trans fats
- Dairy products made from whole milk
(Sources: American Heart Association, 2020; Centers for Disease Control and Prevention, 2023b, 2023c; Grundy et al., 2019)