- Composition of the blood lipoproteins
- The major components of lipoproteins are triacylglycerols, cholesterol, cholesterol esters, phospholipids, and proteins.
- The protein components (called apoproteins) are designated A, B, C, and E.
- least dense of the blood lipoproteins
- they have the most triacylglycerol and the least protein.(MCQ)
- Very-low-density lipoprotein (VLDL)
- more dense than chylomicrons
- still has a high content of triacylglycerol.(MCQ)
- Intermediate-density lipoprotein (IDL)
- isderived from VLDL
- isdenser than VLDL
- hasless than half the amount of triacylglycerol of VLDL.
- has less triacylglycerol than IDL and more protein
- therefore, is denser than the IDL from which it is derived.
- LDL has the highest content of cholesterol and its esters.(MCQ)
- High-density lipoprotein (HDL)
- densest lipoprotein.
- It has the lowest triacylglycerol content and the highest protein (MCQ)content of all the lipoprotein particles.
- Metabolism of chylomicrons
- synthesized in intestinal epithelial cells.
- Their triacylglycerols are derived from dietary lipid
- their major apoprotein (apo) is apo B-48.(MCQ)
- Chylomicrons travel through the lymph into the blood
- Apo C-II,the activator of lipoprotein lipase, and apo Eare transferred to nascent chylomicronsfrom HDL, and mature chylomicrons are formed
- In peripheral tissues, particularly adipose and muscle, the triacylglycerols are digested by lipoprotein lipase(MCQ)
- As the chylomicron loses triacylglycerol, a chylomicron remnant is formed.
- The chylomicron remnants interact with receptors on liver cells and are taken up by endocytosis
- The contents are degraded by lysosomal enzymes, and the products (amino acids, fatty acids, glycerol, cholesterol, and phosphate) are released into the cytosol and reused.
Metabolism of VLDL
- synthesized in the liver(MCQ)
- particularly after a high-carbohydrate meal.
- It is formed from triacylglycerols that are packaged with cholesterol, apoproteins (particularly apo B-100), and phospholipids, and it is released into the blood. (MCQ)
- In peripheral tissues, particularly adipose and muscle, VLDL triacylglycerols are digested bylipoprotein lipase, and VLDL is converted to IDL.(MCQ)
- IDL returns to the liver, is taken up by endocytosis, and is degraded by lysosomal enzymes
- IDL can also be further degraded, forming LDL.
- LDL reacts with receptors on various cells, is taken up by endocytosis, and is digested bylysosomal enzymes.
- Cholesterol, released from cholesterol esters by a lysosomal esterase, can be used for the
- synthesis of cell membranes
- synthesis of bile salts in the liver (MCQ)
- synthesis of steroid hormonesin endocrine tissue.
- Cholesterol – Regulatory effects
- Cholesterol inhibits HMG-CoA reductase(a key enzyme in cholesterol biosynthesis) and,thus, decreases the rate of cholesterol synthesis by the cell.(MCQ)
- Cholesterol inhibitssynthesis of LDL receptors(downregulation) and, thus, reduces the amount of cholesterol taken up by cells.
- Cholesterol activates acyl:cholesterolacyltransferase (ACAT), which converts cholesterolto cholesterol esters for storage in cells.(MCQ)
- Metabolism of HDL
- synthesized by theliver
- released into the blood as small, disk-shaped particles.
- The￼major protein of HDL isapo A.(MCQ)
- Apo C-II and ApoEare donated initially and taken back by HDL
- Apo C-II,which is transferred by HDL tochylomicrons and VLDL, serves as an activator of lipoprotein lipase.
- Apo C-II and apo Earetransferred back to HDL after digestion of triacylglycerols of chylomicrons and VLDL.(MCQ)
- Lecithin:cholesterolacyltransferase (LCAT) reaction
- Cholesterol, obtained by HDL from cell membranes or from other lipoproteins, is converted to cholesterol esterswithin the HDL particle by the lecithin:cholesterolacyltransferase (LCAT) reaction, which is activated by apo A-I.(MCQ)
- A fatty acid from position 2 of lecithin (phosphatidylcholine), a component of HDL, forms an ester with the 3-hydroxyl group of cholesterol, producing lysolecithin and a cholesterolester.
- As cholesterol esters accumulate in the core of the lipoprotein, HDL particles becomespheroids
- HDL transfers cholesterol esters to other lipoproteins in exchange for various lipids.
- Cholesterol ester transfer protein (CETP) mediates this exchange. (MCQ)
- VLDL and other lipoproteins carry the cholesterol esters back to the liver.
- HDL particles and other lipoproteins are taken up by the liver by endocytosis and hydrolyzed by lysosomal enzymes.
- Faste of Cholesterol, released from cholesterol esters
- can be packaged by the liver in VLDL and released into the blood or
- converted to bile salts and secreted into the bile.(MCQ)
- member of the fibrate class of lipid-lowering agents
- activates the transcription of lipoprotein lipase by activating the PPAR (peroxisome proliferator-activated receptors) family of receptors. decreases the level of VLDLs and other triglyceride-rich lipoproteins.(MCQ)
- Tangier disease
- a disease of cholesterol transport.
- Occur because of a mutation in a transport protein, cholesterol cannot properly exit the cell to bind to apo A (forming HDL).
- This results in a very low HDL level.(MCQ)
- LCAT deficiency(MCQ)
- results in an inability to convert cholesterolassociated withHDL to cholesterol esters.
- Ordinarily, these cholesterol esters would be transferred to other lipoproteins, which would then be taken up by receptors in the liver.
- Therefore, by inducing esterification of cholesterol, LCAT is important for the continued removal of cholesterol from the periphery.(MCQ)
- Clinical manifestations include defects in the kidneys, red blood cells, and the cornea of the eyes.
You see a patient who has steatorrhea, with very low levels of chylomicrons and VLDL in the circulation. Circulating triglyceride levels are extremely low. Examination of intestinal epithelial cells shows lipid-laden cells. A possible enzymatic defect leading to these findings is which of the following?
(B) Apolipoprotein CII
8 The answer is C:
MTTP. The patient has abetalipoproteinemia, an absence of apo B-containing proteins in the circulation. This leads to low chylomicron and VLDL levels. The problem is the synthesis of the chylomicrons and VLDL, both of which require the activity of the microsomal triglyceride transfer protein (MTTP). In the absence of MTTP activity, triglycerides cannot be transferred to the core particle as it is being synthesized, leading to little, if any, synthesis of these particles. The intestinal cells become laden with lipids obtained from the diet and those which cannot be exported due to the inability to produce chylomicrons.
Mutations in LPL or apolipoprotein CII will not interfere with chylomicron or VLDL synthesis; mutations in those proteins would lead to an inability to remove triglyceride from those circulating particles. Deficiencies in LCAT or ABC1, which are related to HDL metabolism, would not affect the synthesis of chylomicrons or VLDL.
Cholestyramine acts to lower cholesterol by inhibiting which of the following enzymes/pathways?
(A) HMG-CoA reductase
(B) Hepatic cholesterol synthesis
(C) Release of bile salts from the gall bladder
(D) Enterohepatic circulation reabsorption of bile salts
(E) The production of chylomicrons
1 The answer is D:
Enterohepatic circulation reabsorption of bile salts. Because of the elevated liver enzymes (suggestive of liver damage), a statin would be relatively contraindicated in this patient, as a potential side effect of statins is liver damage. Cholestyramine would be a reasonable alternative to statins. Cholestyramine is one of the “bile acid binders” and prevents the reabsorption of bile salts. Since cholesterol is the precursor of bile salts, and 95% of bile salts are usually reabsorbed back into the enterohepatic circulation, losing bile salts in the feces would require increased synthesis of bile salts, thereby reducing the levels of free cholesterol in the body. Statins work by inhibiting HMG-CoA reductase. Cholestyramine does not reduce hepatic cholesterol synthesis, inhibit the release of bile salts, or interfere with the production of chylomicrons. Its sole action is in the lumen of the intestine, where it binds the bile salts so that they cannot be resorbed and sent back to the liver.
2 Statins are effective due to a direct inhibition of which of the following?
(A) Medium chain acyl-CoA dehydrogenase (MCAD)
(B) HMG-CoA synthase
(C) HMG-CoA reductase
(D) Carnitineacyltransferase 1 (CAT-1)
(E) Citrate lyase
2 The answer is C:
HMG-CoA reductase. The fi rst stage of cholesterol synthesis leads to the production of the intermediate mevalonate. Two molecules of acetyl-CoA condense to form acetoacetyl-CoA which condenses with another acetyl-CoA to form β-hydroxymethylglutaryl-CoA (HMG-CoA). HMGCoAsynthase catalyses this step. Next, HMG-CoA reductase catalyzes the reduction of HMG-CoA to mevalonate. Statins (the class of drugs to which pravastatin belongs) directly inhibit HMG-CoA reductase, so mevalonate cannot be formed and cholesterol synthesis cannot continue. Statins do not inhibit the enzymes MCAD (required for fatty acid oxidation), CAT-1 (required for acyl-CoA transport into the mitochondria), or citrate lyase (needed to provide acetyl-CoA in the cytoplasm). The reactions required to produce HMG-CoA are shown below.
3 A mutation in in which the ability to create conjugated bile salts was greatly impaired leads to which of the following?
(B) Elevated levels of chylomicrons
(C) Deficiency of B vitamins
(D) Reduced pH in the intestinal lumen
(E) Reduced secretion of pancreatic zymogens
3 The answer is A:
The primary reason for synthesizing conjugated bile acids is to lower the pKa of the acid, so that a higher percentage of the acid will be ionized in the intestine. The greater a bile acid is ionized, the more efficient the emulsification is for the digestion of the triglyceride. Without conjugation with glycine or taurine, the pKa of the bile salts is about 6.0; at a pH of 6.0, only 50% of the bile salts will be ionized in the intestinal lumen, which would produce inefficient triglyceride digestion, and the triglyceride content of the stool would increase.
By reducing the pKa to 4.0 (conjugated with glycine) or 2.0 (conjugated with taurine), greater than 99% of the bile acids will be ionized, and triglyceride digestion will be maximal. If an inability to conjugate the bile acids leads to inefficient triglyceride digestion, then intestinal chylomicron formation will be reduced, not elevated (due to reduction of lipid uptake into the enterocyte). Transport of the water soluble B vitamins into the intestinal cells is not dependent on lipid digestion, as is fat-soluble vitamin absorption. The conjugation of bile acids will not affect the pH of the intestinal lumen, nor will it affect the secretion of zymogens from the pancreas to the intestine. The reactions involved in the conjugation of the bile acids are shown below.
4 A patient has enlarged orange tonsils, hepatosplenomegaly, loss of sensation in hands and feet, and clouding of the corneas. His HDL levels are 18 mg/dL. The molecular defect in this patient is present in which of the following proteins?
(A) HMG-CoA reductase
(B) AMP-activated protein kinase
(C) Lecithin cholesterol acyltransferase
(E) Cholesterol ester transfer protein
4 The answer is D:
- The patient has Tangier disease, which is a defect in the ATP-binding cassette protein 1 (ABC1), a transporter in cell membranes whichallows cholesterol efflux from the membrane into the HDL particle. Once inside the HDL particle, the cholesterol is trapped through esterification into a cholesterol ester.
- The HDL particle can then return the cholesterol to the liver for further recycling.
- The defect in the patient is not in
- HMG-CoA reductase (required for the biosynthesis of cholesterol),
- theAMP-activated kinase (a regulator of HMG-CoA reductase),
- LCAT (lecithin-cholesterol acyltransferase, the enzyme which esterifies cholesterol in the HDL particle),
- CETP (cholesterol ester transfer protein, a protein which exchanges HDL cholesterol esters for VLDL triglyceride).
Physiologically, exercise and low energy stores (increased AMP/ATP ratio) activate AMP kinase (AMPK) activity. AMPK, in turn, phosphorylates and inactivates HMG-CoA reductase (HMG-CoAR), target of rapamycin (TOR) and ACC-2. Established drugs (yellow pill) such as the biguanide metformin activate AMPK, whereas statins and rapamycin inhibit HMG-CoAR and TOR, respectively. Experimental compounds (green pill) CP-640186 and TOFA are non-selective inhibitors of ACC, a key enzyme in fatty-acid biosynthesi
- CETP (cholesterol ester transfer protein, a protein which exchanges HDL cholesterol esters for VLDL triglyceride).
An adult male should have HDL levels equal to or greater than 40 mg/dL. A necessary enzyme contributing to HDL’s protective effect is which of the following?
(D) AMP-activated protein kinase
(E) Protein kinase A
5 The answer is B:
- LCAT. HDL is protective, in part, due to its ability to remove excess cholesterol from cell membranes and return it to the liver. In order to accomplish this, the cholesterol, after transport to the HDL particle via the participation of ABC1, needs to be trapped within the core of the HDL particle, and this is accomplished by esterification and converting the cholesterol to a cholesterol ester. LCAT (lecithin cholesterol acyl transferase) is the enzyme that creates a cholesterol ester. The reaction, on page 153, is the transfer of a fatty acid from phosphatidyl choline (lecithin) to cholesterol, creating the cholesterol ester and lysophosphatidyl choline. ACAT (acyl-CoA cholesterol acyl transferase) creates cholesterol esters in cells, but not in the HDL particles. CETP exchanges HDL cholesterol esters for VLDL triglyceride. Protein kinase A is not involved in cholesterol transfer throughout the body. The AMP-activated protein kinase is not utilized in HDL action. The LCAT reaction is shown below.
Statins are ineffective in lowering cholesterol levels in individuals with homozygous familial hypercholesterolemia due to which of the following?
(A) HMG-CoA reductase is resistant to statins
(B) Statins cannot enter the liver cells
(C) LDL receptors are nonfunctional
(D) Reverse cholesterol transport is inoperative in these patients
(E) LCAT is resistant to statin action
7 The answer is C:
LDL receptors are nonfunctional. Statins are effective in lowering circulating cholesterol levels due to a series of events. First, the statins inhibit HMG-CoA reductase, reducing intracellular synthesis of cholesterol. The reduced cholesterol levels in the cell then upregulate the synthesis of LDL receptors, which remove LDL from circulation, thereby reducing circulating cholesterol levels. Familial hypercholesterolemia hypercholesterolemia (FH) is a mutation in the LDL receptor, making the receptor unable to bind LDL. In homozygous familial hypercholesterolemia, both LDL receptor genes are mutated, and the LDL receptors are nonfunctional. Upregulating nonfunctional LDL receptors will not lead to a reduction of LDL in the circulation, so such individuals are resistant to statin action. FH is not due to a resistant HMG-CoA reductase, nor an inability of statins to reach their target. FH is not related to reverse cholesterol transport, nor to LCAT.
A type 1 diabetic who has neglected to take his insulin for a few days displays both hyperglycemia and hypertriglyceridemia. The hypertriglyceridemia is due, in part, to which of the following?
(A) Reduced synthesis of VLDL
(B) Reduced production of apolipoprotein CII
(C) Increased fatty acid oxidation
(D) Reduced secretion of LPL
(E) Increased synthesis of B100
9 The answer is D:
Reduced secretion of LPL.
Insulin release stimulates the secretion of lipoprotein lipase (LPL) from fat and muscle cells such that the capillaries infiltratingthese tissues have the lipase bound to extracellular matrix material.
Then, as the triglyceride-rich particles move through the tissues, they bind to LPL via apolipoprotein CII, and the triglyceride is digested and the fatty acids used by the tissues.
In the absence of insulin, LPL levels are low, and the particles have a longer half-life in circulation due to the reduced rate of digestion, which contributes to hypertriglyceridemia.
If there were reduced synthesis of VLDL, triglycerides in the circulation would be reduced, not increased. Insulin does not alter the rate of apolipoprotein CII production. The release of insulin decreases fatty acid oxidation (promoting fatty acid synthesis), but if increased fatty acid oxidation did occur, then triglycerides would not accumulate in the circulation.
Insulin also does not alter the synthesis of apolipoprotein B100 in the liver, which is required for VLDL synthesis.
10 A 12-year-old female presented with severe abdominal pain and was found to have a markedly elevated plasma triglyceride concentration (750 mg/dL). A lipoprotein analysis revealed elevated levels of chylomicrons and VLDL and reduced levels of HDL. Which protein might be defective in this patient?
(A) Apo B100
(B) Apo B48
(C) Apo CII
(D) Pancreatic lipase
10 The answer is C:
Apo CII. A lack of apolipoprotein CII would mean that lipoprotein lipase could not be activated, and the triglyceride in both chylomicrons and VLDL would be unable to be digested. This would lead to elevated levels of these particles, and a very high serum triglyceride level. Since VLDL is not being converted to IDL or LDL cholesterol levels are not elevated. Defects in either apo B100 or apo B48 would lead to a loss of either VLDL or chylomicrons, which is not observed. A defect in pancreatic lipase would lead to steatorrhea, as the dietary triglycerides would not be able to be digested. A defect in LCAT would affect HDL metabolism, but not triglyceride metabolism
An initiating factor for the development of the ATHEROSCLEROTIC blockage of coronaries is which of the following?
(B) Oxidized LDL
(E) Oxidized HDL
12 The answer is B:
Oxidized LDL. Oxidized LDL is taken up by macrophages, which eventually turn into foam cells in the development of an atherosclerotic plaque. The higher one’s LDL levels are, the more likely that oxidized LDL will form, leading to plaque formation. The receptor which recognizes and takes up oxidized LDL, SR-A1, is not downregulated, so the macrophage has an unlimited capacity to take up and store the oxidized LDL. Plaque formation does not occur due to elevated levels of nonoxidized LDL, HDL of any form, or triglyceride
A 32 -year-old male patient, with a BMI of 34, has a total cholesterol of 450 mg/dL and triglycerides of 610 mg /dL. He exhibits planar xanthomas and has already had one angioplasty last year. This patient may be exhibiting a rare autosomal recessive disorder which generates a mutation in which of the following proteins?
(B) Apolipoprotein CII
(C) Apolipoprotein E
(D) Apolipoprotein B100
(E) Apolipoprotein B48
13 The answer is C:
Apolipoprotein E. The patient has dysbetalipoproteinemia, a mutation in apolipoprotein E, such that the patient exhibits the rare E2 form instead of the normal E3 form. Apolipoprotein E has affinity for the LDL receptor and the LDL receptor-related protein and, as such, is important for chylomicron remnant and IDL uptake from the circulation by the liver. With the homozygous E2 form, binding of the particles to their receptors is weak, and the particles circulate longer than normal, contributing to the high cholesterol and triglyceride levels seen in the circulation. Only about 10% of the individuals who are homozygous for E2 will develop this condition, and in those, obesity (BMI of 34) is a key factor which links the condition to the mutation. This disorder is not a problem with lipoprotein lipase (LPL) digesting triglycerides from particles, so neither LPL nor apo CII is defective. As both chylomicrons and VLDL are produced, it is not a defect in either apo B48 or B100 production or function.
24. The lipoprotein that contains the lowest amount of protein is called:
ANS: 24. A. Chylomicrons have the lowest amount of protein. Protein is denser than lipid. It is the largest and the least dense of the lipoprotein particles. Because of the least density, they also readi float on top of stored plasma and form a creamy layer.
25. Which lipoprotein is the major transporter of endogenous triacylglycerides from liver to peripheral tissues:
ANS: 25. B. Chylomicrons are the major transporters of dietary lipids to hepatic and peripheral cells. Very low density lipoproteins (VLDI ) are the major transporter of endogenous triacylglycerides from the liver to peripheral tissues. High density lipoproteins (HDL) are the transporter of cholesterol from tissues to liver. Low density lipoprotein (LDL) carries cholesterol to peripheral tissues.
26. Lipoprotein Lipase:
A. Hydrolyses cholesterol
B. Hydrolyses phospholipids
C. Hydrolyses triacylglycerol
D. Hydrolyses carbohydrates
ANS: 26. C. Lipoprotein lipase is found on the luminal surface of the capillary endothelium. When ever the chylomicrons and VLDL pass through the capillaries of tissues, lipoprotein lipase is activated by an apolipoprotein C-II. It hydrolyses triacylglycerol to glycerol and free fatty acids.
27. Which one of the following apolipoprotein activate lecithin- cholesterol acyltransferase:
ANS: 27. A. Apolipoprotein A-I activates lecithin – cholesterol acyl transferase. A-H activates hepatic lipase. C-II activates lipoprotein lipase and apo E bind to the LDL receptor and increases uptake of LDL and remnant particles of chylomicrons.
28. Elevated plasma concentration of chylomicrons and triacyl- glycerols are seen in:
A. Type I hyperlipoproteinemia
B. Type II a hyperlipoproteinemia
C. Type II b hyperlipoproteinemia
D. Type V hyperlipoproteinemia
ANS: 28. A. Type I hyperlipoproteinemia is due to the deficiency of lipoprotein lipase. Type II a – absence of LDL receptors, LDL and cholesterol concentration in the plasma is increased. Type lib is due to overproduction of apo B thereby increased VLDL, LDL, cholesterol and triacylglycerol. Type V is due to the overproduction of VLDL thereby increased VLDL and chylomicrons.
A. Decrease cholesterol levels in plasma
B. Increase cholesterol levels in plasma
C. Lower plasma triacylglycerols
D. Decrease plasma LDL Levels
ANS: 29. C. Statins decreases cholesterol levels in plasma by inhibiting HMG- CoA reductase. Benzafibrate by activating lipoprotein lipase enzyme lowers plasma triacylglycerols.
Physiology of Lipoprotein Metabolism
Lipoproteins, Apolipoproteins, and Familial Dyslipidemias Made Simple!
This video covers the basics of the lipoproteins, their pathway in the body, apolipoproteins, and familial dyslipidemias.
Lipids and Lipoproteins
What are lipoproteins? These slides give a general introduction to lipoproteins and their structure.
Lipoprotein Physiology: Overview (1/4)
Lipoprotein Physiology: Chylomicron (2/4)
Lipoprotein Physiology: LDL (3/4)
Lipoprotein Physiology: HDL (4/4)