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π’»π“Šπ“ƒπ’Ήπ’Άπ“‚π‘’π“ƒπ“‰π’Άπ“π“ˆ π‘œπ’» 𝓉𝒽𝑒 𝓁𝒾𝓋𝒾𝓃𝑔 𝒸𝑒𝓁𝓁 > Lipid transport > Flashcards

Lipid transport Flashcards

1
Q

describe the properties of free fatty acids

A

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

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2
Q

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

A

β†’if they are unbound then they will act as detergents

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3
Q

what is a lipoprotein?

A

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

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4
Q

what is the structure of a lipoprotein?

A

β†’membrane consists of phospholipids and cholesterol, and large apolipoproteins.

β†’In the center, there are cholesterol esters and triacylglycerol.

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5
Q

what are the 5 lipoproteins?

A 
β†’Chylomicrons 
β†’Very Low-Density Lipoproteins (VLDLs) 
β†’ Low-Density Lipoproteins (LDLs) -
β†’Intermediate Density Lipoproteins (IDLs) 
β†’ High-Density Lipoproteins (HDLs)
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6
Q

what are the compositions of the 5 lipoproteins?

A

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

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7
Q

what are apoproteins or apolipoproteins?

A

β†’proteins that bind lipids together to form lipoproteins.

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8
Q

what are the functions of apoproteins?

A

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

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9
Q

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

A

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

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

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10
Q

what is an example of apoproteins involved in tissue targeting?

A

β†’ APO B100 and APO E bind to the LDL receptor

β†’ APO E binds to the HDL receptor

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11
Q

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

A

β†’CHYLOMICRONS: B48, APO C2, C3 and E

β†’VLDL: B100, APO C1, C2, C3 and E

β†’ LDL: B100

β†’ IDL: B100, APO E

β†’HDL: APO A1, A2, C1, C3, D and E

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12
Q

how does the synthesis of chylomicrons happen?

A

β†’ formed in the cells that line the gut.

β†’In the lumen of the gut, triglycerides are broken down to fatty acids.

β†’the triglycerides and monoacylglycerols are brought into the mucosal cell and reformed into triacylglycerides.

β†’They then combine with other lipids and proteins in the cell to form chylomicrons.

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13
Q

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

A

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

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

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14
Q

where are digested proteins and carbohydrates delivered?

A

β†’digested proteins and carbohydrates are released into the portal vein and delivered directly to the liver.

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15
Q

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

A

β†’when first formed, the only apoprotein chylomicrons consist of are the ApoB48.

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

β†’this forms a mature chylomicron.

β†’this donation occurs in the SER.

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16
Q

what are chylomicrons for and how are they removed?

A

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

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

β†’ their remnants are removed by the liver, with the help of Apo E

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17
Q

what do chylomicrons contain and what is their lifetime?

A

β†’they contain fat soluble vitamins such as Vitamins A and E

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

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18
Q

why do chylomicrons have a low density?

A

β†’they have a low density due to a high number of triglycerides

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19
Q

how does lipoprotein lipase work?

A

β†’LPLs bind to and are activated by Apo C2.

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

20
Q

where are LPLs found?

A

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

21
Q

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

A

β†’There are different isoforms of the enzyme expressed in the different tissue.

β†’mammary, muscle or adipose tissue.

β†’The Km of the LPL isoform in adipocytes is greater than in muscle.

22
Q

what is hyperlipidaemia?

A

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

23
Q

what are the different types of hyperlipidaemia?

A

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

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

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

24
Q

what are VLDLs for and what are they metabolized by?

A

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

β†’ they’re metabolised by LPL as they circulate

25
Q

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

A

β†’TG half-life is 15-60 minutes

β†’ their formation is enhanced by: dietary carbohydrates, circulating FFAs, alcohol, raised insulin and decreased glucagon

26
Q

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

A

β†’VLDLs are synthesised in the liver, ER and Golgi.

β†’when released as nascent VLDLs, they only have Apo B100 apoprotein.

β†’when they interact with HDL, the HDL donates Apo C2 and Apo E to the VLDL, making it mature.

27
Q

what is the difference between Apo B100 and Apo B48?

A

β†’ both synthesised from the same gene.

β†’ B100 is 100% of the gene

β†’B48 is 48% of that gene.

β†’Their expression is differentially regulated within the cell types.

28
Q

what are the two fates of VLDLs?

A

β†’when it’s lost the majority of its triglycerides, its remnants will return to the liver (removed by Apo E).

β†’ or form IDLs (via Lipase), and those IDLs may be removed by the liver

β†’or may be converted to LDLs, which will be removed by the liver and by non-hepatic tissue for steroid biosynthesis.

29
Q

what is the function of LDLs?

A

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

30
Q

what are the three ways in which HDLs are made?

A

β†’in the liver and intestines
β†’ by budding from VLDL and chylomicrons
β†’ from the free Apo A1

31
Q

how do HDLs remove cholesterol from circulation?

A

β†’they contain an enzyme called Lecithin-Cholesterol AcylTransferase (LCAT)

β†’ LCAT modifies free cholesterol and then retains it within the HDL.

β†’This prevents the cholesterol from diffusing out of the HDL.

32
Q

how does HDL pick up cholesterol?

A

β†’the process by which it picks up cholesterol is known as Reverse Cholesterol Transport.

β†’this occurs in the plasma and on endothelial cells.

β†’ 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.

33
Q

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

A

β†’HDLs are commonly referred to as β€˜good cholesterol’, while LDLs are referred to as β€˜bad cholesterol’.

β†’The HDL/LDL is used diagnostically to assess the susceptibility to heart disease.

β†’Normal individuals have a ratio of 3.5.

34
Q

how are lipoproteins removed from circulation?

A

β†’Lipoproteins are removed from the circulation by Receptor-Mediated Endocytosis.

35
Q

describe receptor mediated endocytosis in relation to LDL

A

1)
β†’LDLs in the circulation can bind to specific receptors expressed on endothelial cells.

2)
β†’The receptor and LDL are endocytosed, with the membrane pinching off to form a vesicle.

3)
β†’The vesicle fuses with endosomes.
β†’The endosomes contain enzymes responsible for the breakdown of protein and metabolism of lipids
β†’receptor is recycled and re-inserted into the membrane.

4)
β†’There will be a further fusion with a lysosome to provide more enzymes (hydrolytic)

5)
β†’The cholesterol esters are converted to cholesterol
β†’which diffuse out into the cytoplasm
β†’where they are immediately esterified
β†’(since free cholesterol is not desirable within a cell, unless associated with a membrane).

β†’The triglycerides will be broken down to give fatty acids, which can be further metabolised, and amino acids will also be broken down.

36
Q

how is receptor mediated endocytosis regulated?

A

β†’regulated by the intracellular concentration of cholesterol

β†’which regulates the expression of new and existing receptors on the membrane.

β†’With increased cholesterol, HMG-CoA reductase activity is inhibited.

β†’HMG-CoA reductase reduces the LDL receptor expression.

37
Q

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

A

β†’ present on VLDLs and LDLs
β†’ binds to LDL receptors
β†’distributed in the liver

38
Q

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

A

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

39
Q

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

A

β†’ Familial Hypercholesterolemia (FH).

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

40
Q

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

A

β†’high-affinity LDL receptor
β†’ low-affinity scavenger receptor

β†’They’re present on endothelial cells, macrophages and VSMC (vascular smooth muscle cells).

β†’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.

41
Q

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

A

HORMONAL REGULATION:
β†’insulin
β†’cortisol
β†’ thyroid hormones

LDL EXPRESSION:
β†’oestrogen

NUTRITIONAL STATUS:
β†’decreased synthesis during fasting
β†’ increased by dietary fats
β†’unsaturated fats best

42
Q

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

A

DIABETES MELLITUS:
β†’increased FFA metabolism
β†’ decreased chylomicron and VLDL utilisation

GENE DEFECTS:
β†’gene defects in apolipoproteins, enzymes or receptors
β†’ leading to hypercholesterolemia, atherosclerosis, etc.

OBESITY:
β†’can cause hypertension, NIDDM (noninsulin-dependent diabetes mellitus), hyperlipidaemia and hyperglycaemia

43
Q

where do chylomicrons transport fat?

A

small intestine to capillaries

44
Q

where do chylomicron remnants transport fat?

A

from the capillaries to the liver

45
Q

where do IDL and LDL transport fat?

A

capillaries to extra hepatic tissue

46
Q

where does HDL transport fat?

A

extra hepatic tissue to liver

π’»π“Šπ“ƒπ’Ήπ’Άπ“‚π‘’π“ƒπ“‰π’Άπ“π“ˆ π‘œπ’» 𝓉𝒽𝑒 𝓁𝒾𝓋𝒾𝓃𝑔 𝒸𝑒𝓁𝓁 (34 decks)

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