Lipid transport

Question 1

describe the properties of free fatty acids

Answer 1

→they’re formed from triacylglycerides stored in adipose tissue
→ it circulates bound to protein as a Na+ salt, particularly the albumin protein
→ saturation occurs at about 2 mM of fatty acid molecules
→ it enters the cell by simple diffusion
→ the intracellular concentration of free fatty acids is kept low

Question 2

why do free fatty acids (FFAs) need to travel bound to a protein?

Answer 2

→if they are unbound then they will act as detergents

Question 3

what is a lipoprotein?

Answer 3

→biochemical assembly whose purpose is to transport hydrophobic lipid molecules in water, in blood or extracellular fluid.

Question 4

what is the structure of a lipoprotein?

Answer 4

→membrane consists of phospholipids and cholesterol, and large apolipoproteins.

→In the center, there are cholesterol esters and triacylglycerol.

Question 5

what are the 5 lipoproteins?

Answer 5

→Chylomicrons 
→Very Low-Density Lipoproteins (VLDLs) 
→ Low-Density Lipoproteins (LDLs) -
→Intermediate Density Lipoproteins (IDLs) 
→ High-Density Lipoproteins (HDLs)

Question 6

what are the compositions of the 5 lipoproteins?

Answer 6

→CHYLOMICRONS: most (90-95%) triglycerides, so the least dense
→VLDLs: mostly triglycerides (53%)
→LDLs: mostly (50%) cholesterol
→ IDLs: intermediate in all (highest is triglycerides, 31%)
→HDLs: mostly (49%) protein

Question 7

what are apoproteins or apolipoproteins?

Answer 7

→proteins that bind lipids together to form lipoproteins.

Question 8

what are the functions of apoproteins?

Answer 8

→structural functions (the backbone of the lipoproteins)
→ to solubilise lipids (lipoproteins allow lipids to travel in aqueous solution)
→ act as enzymes or enzyme cofactors
→ tissue targeting

Question 9

what is an example of apoproteins acting as enzymes or enzyme cofactors?

Answer 9

→APO C2 activates lipoprotein lipase (LPL, breaks down fat in the form of triglycerides, so a lipoprotein expressing this apoprotein will lose its triglycerides)

→ APO A1 activates Lecithin-Cholesterol AcylTransferase (LCAT, converts free cholesterol into cholesteryl esters)

Question 10

what is an example of apoproteins involved in tissue targeting?

Answer 10

→ APO B100 and APO E bind to the LDL receptor

→ APO E binds to the HDL receptor

Question 11

what are the apoproteins involved in the composition of the different lipoproteins?

Answer 11

→CHYLOMICRONS: B48, APO C2, C3 and E

→VLDL: B100, APO C1, C2, C3 and E

→ LDL: B100

→ IDL: B100, APO E

→HDL: APO A1, A2, C1, C3, D and E

Question 12

how does the synthesis of chylomicrons happen?

Answer 12

→ formed in the cells that line the gut.

→In the lumen of the gut, triglycerides are broken down to fatty acids.

→the triglycerides and monoacylglycerols are brought into the mucosal cell and reformed into triacylglycerides.

→They then combine with other lipids and proteins in the cell to form chylomicrons.

Question 13

how and why are chylomicrons delivered directly to the lymph system?

Answer 13

→Chylomicrons are secreted into the lymphatics which carries them via the thoracic duct to the superior vena cava.

→By this pathway, dietary fats avoid the direct delivery to the liver and instead are made available to the extrahepatic tissue.

Question 14

where are digested proteins and carbohydrates delivered?

Answer 14

→digested proteins and carbohydrates are released into the portal vein and delivered directly to the liver.

Question 15

how does a nascent chylomicron become a mature chylomicron (in terms of apoproteins)?

Answer 15

→when first formed, the only apoprotein chylomicrons consist of are the ApoB48.

→as it circulates, it interacts with HDL and the HDL donates certain apoproteins to the nascent chylomicron, primarily Apo C2 and Apo E.

→this forms a mature chylomicron.

→this donation occurs in the SER.

Question 16

what are chylomicrons for and how are they removed?

Answer 16

→they’re important for transporting exogenous (dietary) lipids from gut around the circulation

→ they reflect meal composition (if a fatty meal is ingested, there will be many chylomicrons of that composition)

→ their remnants are removed by the liver, with the help of Apo E

Question 17

what do chylomicrons contain and what is their lifetime?

Answer 17

→they contain fat soluble vitamins such as Vitamins A and E

→their lifetime in the circulation is about one hour (the triglyceride’s is about 5 minutes)

Question 18

why do chylomicrons have a low density?

Answer 18

→they have a low density due to a high number of triglycerides

Question 19

how does lipoprotein lipase work?

Answer 19

→LPLs bind to and are activated by Apo C2.

→A lipoprotein binds to the LDL, and the triglycerides in it are broken down into monoacylglycerols and fatty acids.

Question 20

where are LPLs found?

Answer 20

→Lipoprotein Lipases levels vary with the tissue, found in cells that utilise a lot of fats.

Question 21

where are the 3 isoforms of LPL found and in which is the Km greatest?

Answer 21

→There are different isoforms of the enzyme expressed in the different tissue.

→mammary, muscle or adipose tissue.

→The Km of the LPL isoform in adipocytes is greater than in muscle.

Question 22

what is hyperlipidaemia?

Answer 22

→hyperlipidaemia is abnormally elevated levels of any or all lipids/lipoproteins in the blood.

Question 23

what are the different types of hyperlipidaemia?

Answer 23

TYPE 1:
→ caused by either a deficiency in lipoprotein lipase or Apo C2
→characterised by high plasma triglyceride

TYPE 2: Characterised by high LDL
→ most caused by a genetic defect in the synthesis processing or function of the LDL receptor

→TYPE 4: Most common results in increased VLDL concentrations often due to obesity or alcohol abuse

Question 24

what are VLDLs for and what are they metabolized by?

Answer 24

→they’re responsible for transporting endogenously-synthesised (synthesised in the liver) lipids

→ they’re metabolised by LPL as they circulate

Question 25

what is VLDL half life and what is their fomation enhanced by?

Answer 25

→TG half-life is 15-60 minutes → their formation is enhanced by: dietary carbohydrates, circulating FFAs, alcohol, raised insulin and decreased glucagon

Question 26

how does VLDL convert to a mature VLDL (in terms of apoproteins) and where is VLDL synthesized?

Answer 26

→VLDLs are synthesised in the liver, ER and Golgi. →when released as nascent VLDLs, they only have Apo B100 apoprotein. →when they interact with HDL, the HDL donates Apo C2 and Apo E to the VLDL, making it mature.

Question 27

what is the difference between Apo B100 and Apo B48?

Answer 27

→ both synthesised from the same gene. → B100 is 100% of the gene →B48 is 48% of that gene. →Their expression is differentially regulated within the cell types.

Question 28

what are the two fates of VLDLs?

Answer 28

→when it's lost the majority of its triglycerides, its remnants will return to the liver (removed by Apo E). → or form IDLs (via Lipase), and those IDLs may be removed by the liver →or may be converted to LDLs, which will be removed by the liver and by non-hepatic tissue for steroid biosynthesis.

Question 29

what is the function of LDLs?

Answer 29

→they're the major carrier of cholesterol → they're metabolised slowly - 3 days →they carry cholesterol to the periphery and regulate de novo synthesis → they contain one Apo B100, which can bind to a specific receptor on hepatocytes

Question 30

what are the three ways in which HDLs are made?

Answer 30

→in the liver and intestines → by budding from VLDL and chylomicrons → from the free Apo A1

Question 31

how do HDLs remove cholesterol from circulation?

Answer 31

→they contain an enzyme called Lecithin-Cholesterol AcylTransferase (LCAT) → LCAT modifies free cholesterol and then retains it within the HDL. →This prevents the cholesterol from diffusing out of the HDL.

Question 32

how does HDL pick up cholesterol?

Answer 32

→the process by which it picks up cholesterol is known as Reverse Cholesterol Transport. →this occurs in the plasma and on endothelial cells. → to signal this, they express the ABCA1 transporter, which moves cholesterol from the extracellular surface of the membrane and interacts with the Apo A1 on the HDLs to transport the cholesterol away.

Question 33

what is the significance of the HDL/LDL ratio and what is the normal ratio?

Answer 33

→HDLs are commonly referred to as 'good cholesterol', while LDLs are referred to as 'bad cholesterol'. →The HDL/LDL is used diagnostically to assess the susceptibility to heart disease. →Normal individuals have a ratio of 3.5.

Question 34

how are lipoproteins removed from circulation?

Answer 34

→Lipoproteins are removed from the circulation by Receptor-Mediated Endocytosis.

Question 35

describe receptor mediated endocytosis in relation to LDL

Answer 35

1) →LDLs in the circulation can bind to specific receptors expressed on endothelial cells. 2) →The receptor and LDL are endocytosed, with the membrane pinching off to form a vesicle. 3) →The vesicle fuses with endosomes. →The endosomes contain enzymes responsible for the breakdown of protein and metabolism of lipids →receptor is recycled and re-inserted into the membrane. 4) →There will be a further fusion with a lysosome to provide more enzymes (hydrolytic) 5) →The cholesterol esters are converted to cholesterol →which diffuse out into the cytoplasm →where they are immediately esterified →(since free cholesterol is not desirable within a cell, unless associated with a membrane). →The triglycerides will be broken down to give fatty acids, which can be further metabolised, and amino acids will also be broken down.

Question 36

how is receptor mediated endocytosis regulated?

Answer 36

→regulated by the intracellular concentration of cholesterol →which regulates the expression of new and existing receptors on the membrane. →With increased cholesterol, HMG-CoA reductase activity is inhibited. →HMG-CoA reductase reduces the LDL receptor expression.

Question 37

what lipoproteins is Apo B100 presented on, what does it bind to and where is it distributed, tissue-wise?

Answer 37

→ present on VLDLs and LDLs → binds to LDL receptors →distributed in the liver

Question 38

what lipoproteins is Apo E presented on, what does it bind to and where is it distributed, tissue-wise?

Answer 38

→present on VLDLs, HDLs and chylomicrons → binds to LDL receptors and other proteins → distributed in the liver It is also presented on LDLs → distributed on endothelial cells and macrophages

Question 39

what is an example of when there is a loss of LDL receptor function?

Answer 39

→ Familial Hypercholesterolemia (FH). For homozygous individuals: → loss of LDL receptor function, they have 4x the normal cholesterol serum levels → (800 mg/ml to 200mg/ml) → they develop blocked arteries (atherosclerosis) → they tend to die young from heart attacks → the de novo synthesis is not regulated by LDL → A single amino acid substitution prevents the localisation of the LDL receptor to the coated pits.

Question 40

what are the two types of receptors and where are they present?

Answer 40

→high-affinity LDL receptor → low-affinity scavenger receptor →They're present on endothelial cells, macrophages and VSMC (vascular smooth muscle cells). →The low-affinity scavenger receptor is activated when the plasma LDL levels are high, or when it is chemically modified (ie. oxidised). It is not regulated by cholesterol.

Question 41

what are the three ways in which lipoprotein levels are regulated?

Answer 41

HORMONAL REGULATION: →insulin →cortisol → thyroid hormones LDL EXPRESSION: →oestrogen NUTRITIONAL STATUS: →decreased synthesis during fasting → increased by dietary fats →unsaturated fats best

Question 42

what are 3 situations where there are abnormalities in lipid transport?

Answer 42

DIABETES MELLITUS: →increased FFA metabolism → decreased chylomicron and VLDL utilisation GENE DEFECTS: →gene defects in apolipoproteins, enzymes or receptors → leading to hypercholesterolemia, atherosclerosis, etc. OBESITY: →can cause hypertension, NIDDM (noninsulin-dependent diabetes mellitus), hyperlipidaemia and hyperglycaemia

Question 43

where do chylomicrons transport fat?

Answer 43

small intestine to capillaries

Question 44

where do chylomicron remnants transport fat?

Answer 44

from the capillaries to the liver

Question 45

where do IDL and LDL transport fat?

Answer 45

capillaries to extra hepatic tissue

Question 46

where does HDL transport fat?

Answer 46

extra hepatic tissue to liver