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Questions and Answers
What is a possible explanation for the presence of high levels of LDL in a young person?
What is the primary mechanism by which statins reduce cholesterol synthesis?
Which of the following is a consequence of oxidized LDL uptake by macrophages?
What is the initial approach to treating hyperlipoproteinemias?
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What is the half-life of LDL in the blood compared to VLDL and IDL?
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Which of the following is associated with atherosclerosis?
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What is the purpose of LDL receptor expression in cells?
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What is the role of ApoB-100 in LDL metabolism?
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How do HDL particles acquire cholesterol and phospholipid from other lipoproteins?
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What is the ideal ratio of total cholesterol to HDL-cholesterol for a healthy individual?
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What is the clinical significance of a high level of LDL-cholesterol in the blood?
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What is the significance of xanthelasma in the diagnosis of hyperlipoproteinaemia?
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What is the purpose of the LDL receptor-mediated endocytosis pathway?
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What is the ideal range for triglyceride levels in a fasted sample?
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What percentage of lipids in the blood are carried as lipoprotein particles?
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What is the primary function of apolipoprotein in lipoprotein particles?
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Which of the following is a characteristic of chylomicrons?
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What is the clinical significance of a milky appearance in serum?
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Which of the following lipoprotein particles is responsible for delivering cholesterol to peripheral tissues?
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What is the role of apoC in chylomicron metabolism?
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What is the consequence of a deficiency in apoE?
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What is the primary source of cholesterol in the body?
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What is the clinical significance of high levels of VLDL in the blood?
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What is the primary function of HDL in the body?
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Study Notes
Lipoprotein Metabolism
- LDL enters cells by receptor-mediated endocytosis, where cells requiring cholesterol express LDL receptors on their membrane, and ApoB-100 on LDL acts as a ligand for LDL receptors.
- The receptor/LDL complex is taken into the cell by endocytosis into endosomes, which fuse with lysosomes to release cholesterol and fatty acids.
- LDL receptor expression is controlled by cholesterol concentration in the cell, and clinically, defects in LDL receptors result in elevated blood cholesterol and cardiovascular disease.
HDL Metabolism
- HDL synthesis occurs in the liver and intestine, with nascent HDL particles forming from low triacylglycerol levels.
- HDL particles can also "bud off" from chylomicrons and VLDLs as they are digested by lipoprotein lipase, and free apoA-I can acquire cholesterol and phospholipid from other lipoproteins and cell membranes to form nascent-like HDL.
- Nascent HDL accumulates phospholipids and cholesterol from cells lining blood vessels, and the hollow core progressively fills, taking on a more globular shape, with excess cholesterol secreted in the bile.
Cholesterol Blood Test
- Total cholesterol (TC) should be ideally 5 mmol/L or less.
- Non-HDL cholesterol (total cholesterol minus HDL-cholesterol) should be ideally 4 mmol/L or less.
- LDL-cholesterol (LDL-C) is considered "bad" and should be ideally 3 mmol/L or less.
- HDL-cholesterol (HDL-C) is considered "good" and should be ideally over 1 mmol/L (men) and over 1.2 mmol/L (women).
- The total cholesterol:HDL-C ratio is a risk indicator, with a ratio above 6 considered high risk.
Hyperlipoproteinaemias
- Clinical signs of hypercholesterolaemia include high levels of cholesterol in the blood, cholesterol depositions in various areas of the body, such as xanthelasma, tendon xanthoma, and corneal arcus.
- Factors that can affect cholesterol levels include alcohol consumption, hypothyroidism, liver disease, and nephrotic syndrome.
LDL and Clinical Relevance
- LDL has a longer half-life in blood than VLDL or IDL.
- LDL is more susceptible to oxidative damage, and oxidised LDL is taken up by macrophages, which can transform to foam cells and contribute to the formation of atherosclerotic plaques.
- Raised serum LDL is associated with atherosclerosis and plaque formation in large blood vessels.
Treatment of Hyperlipoproteinemias
- The first approach to treatment involves dietary changes, such as reducing cholesterol and saturated lipids, and increasing fibre intake, as well as lifestyle changes, such as increasing exercise and stopping smoking.
- If this approach is unsuccessful, drugs may be used, such as statins, which reduce cholesterol synthesis by inhibiting HMG-CoA reductase, and bile salt sequestrants, which bind bile salts in the GI tract, forcing the liver to produce more bile acids using more cholesterol.
Lipids
- Lipids are a structurally diverse group of compounds that are hydrophobic and insoluble in water, requiring transport in the blood bound to carriers.
- Approximately 38% of the calories in a healthy diet come from fat, and current recommendations suggest that fat should provide no more than 30% of the total calories.
Lipoproteins - Structure
- Lipoproteins consist of phospholipid, cholesterol, cholesterol esters, proteins, and triacylglycerol, and are classified into five distinct classes based on density: chylomicrons, VLDL, IDL, LDL, and HDL.
Triacylglycerol
- Triacylglycerols are the major fat in the human diet, consisting of a glycerol backbone to which three fatty acids are esterified.
- Digestion involves hydrolysis to fatty acids and 2-monoacylglycerol in the lumen of the intestine.
Phospholipids
- Phospholipids are important components of lipoproteins, with various classes and functions.
Cholesterol
- Cholesterol is an essential component of membranes, modulating fluidity, and is a precursor of steroid hormones and bile acids.
- Some cholesterol is obtained from the diet, but most is synthesised in the liver, and is transported around the body as cholesterol ester.
Apolipoproteins
- Apolipoproteins are a class of proteins associated with lipoprotein particles, with six major classes: A, B, C, D, E, and H.
- Apolipoproteins can be integral or peripheral, and play structural and functional roles, including packaging water-insoluble lipid and acting as co-factors for enzymes and ligands for cell surface receptors.
Lipoprotein Classes
- The five distinct classes of lipoproteins are named according to density, with chylomicrons being the least dense and HDL being the most dense.
- Each class contains variable content of apolipoprotein, triacylglycerol, cholesterol, and cholesterol ester.
Chylomicrons
- Chylomicrons are formed by enterocytes lining the small intestine, combining triacylglycerols from food with specific apoproteins.
- They carry lipids from the diet to tissue, especially adipose tissue, and are normally only present in the blood for 4-6 hours after a meal, before being cleared.
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Description
Learn about the metabolism of VLDL, IDL, and LDL, including receptor-mediated endocytosis, and the role of HDL in lipid metabolism. Understand the regulation of LDL receptor expression and its clinical implications.
