Lipids – digestion and absorption,
blood plasma lipids, lipoproteinsblood plasma lipids, lipoproteins
Biochemistry II
Lecture 1 2008 (J.S.)
Triacylglycerols (as well as free fatty acids and both free and
esterified cholesterol) are very hydrophobic. They are not
soluble in water unless they are emulsified and/or included insoluble in water unless they are emulsified and/or included in
micelles in the presence of tensides.
Lipids in the diet
Western diet contains 40 % of lipids or more.
From that amount, approx. 90 % triacylglycerols,From that amount, approx. 90 % triacylglycerols,
phospholipids, esterified and free cholesterol,
glycolipids, and lipophilic vitamins.glycolipids, and lipophilic vitamins.
In the mouth and stomach, a negligable amount of triacylglycerol
may be hydrolysed by the action of lingual and gastric lipase,may be hydrolysed by the action of lingual and gastric lipase,
particularly in sucklings.
Mechanical action of the stomach converts dietary lipids into anMechanical action of the stomach converts dietary lipids into an
emulsion containing droplets about 1 m in diameter.
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In the intestine,In the intestine,
hydrogen carbonate secreted by pancreas raise pH to the value
~ 6. In the presence of bile acids, fat droplets form mixed micelles
(< 20 nm). The protein colipase, secreted along with lipase, binds to(< 20 nm). The protein colipase, secreted along with lipase, binds to
the dietary fat and to the lipase (1:1) causing it to be more active.
Pancreatic lipase hydrolyzes fatty acids from positions 1 and 3 ofPancreatic lipase hydrolyzes fatty acids from positions 1 and 3 of
triacylglycerols, producing free fatty acids and 2-monoacylglycerols.
The pancreatic secretion also contains cholesterol esterase that removeThe pancreatic secretion also contains cholesterol esterase that remove
fatty acids from cholesterol esters and phospholipases that digest
phospholipids to their components.phospholipids to their components.
Lipid absorption through the brush border microvilli of the enterocytes
lining the lumen is either preceded by dissociation of the micelles orlining the lumen is either preceded by dissociation of the micelles or
the micelles enter the cell by a channel (protein NPC1L1).
Short and medium chain fatty acids (C4 to C12) don't require bile acids forShort and medium chain fatty acids (C4 to C12) don't require bile acids for
their absorption.
The bile acids, which remain in the intestine, are extensively absorbed
when they reach the ileum.
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when they reach the ileum.
The mixed micellesThe mixed micelles
in the chyme are composed, in varying proportions, of the fatty acids (FFA),
mono- and diacylglycerols (MG and DG), perharps some unhydrolysedmono- and diacylglycerols (MG and DG), perharps some unhydrolysed
triacylglycerol (TG), and anions of bile acids, together with minor components
of the diet such as phospholipids, free cholesterol, and fat-soluble vitamins.
Intestinal lumen Mucosal cell (enterocyte)
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Within the mucosal cells, triacylglycerols are resynthesized (the details are
given in Biochemistry I – Metabolism of lipidsgiven in Biochemistry I – Metabolism of lipids
INTESTINAL LUMEN ENTEROCYTES (epithelial cells of intestinal mucosa)
Triacylglycerols
INTESTINAL LUMEN ENTEROCYTES (epithelial cells of intestinal mucosa)
Phospholipids, cholesterol
Apolipoproteins B and A-I
Triacylglycerols
Apolipoproteins B48 and A-I
TriacylglycerolsTriacylglycerols
(resynthesized from
activated components
in the smooth ER)
2Chylomicrons
secreted (exocytosis) from the mucosal cells enter the chyle
of the lymphatic lacteals. Thoracic duct delivers chylomicrons into the blood.
in the smooth ER)
of the lymphatic lacteals. Thoracic duct delivers chylomicrons into the blood.
Short-chain fatty acids glycerol may enter the branches of the portal vein and
are transported to the liver bound to plasma albumin..
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are transported to the liver bound to plasma albumin..
Plasma lipids
Total concentrations of different lipid classes:Total concentrations of different lipid classes:
Approx.
M
Approx. median
value of c
Recommended
cut-off point
Mole fraction
of total FA
Approx. mass
concn. ρMr value of c cut-off point of total FA concn. ρ
Triacylglycerols 860 1.5 mmol/l 2.3 mmol/l 0.35 1.3 g/l
(Phospholipids) 750 (2,5 mmol/l) – 0.30 (2.0 g/l)
Cholesterol, total 385 5.0 mmol/l
desirable < 5.2 mmol/l
0.30 2.0 g/lCholesterol, total 385 5.0 mmol/l
(high risk > 6.2 mmol/l)
0.30 2.0 g/l
Non-esterified FA 260 0.5 mmol/l – 0.05 0.1 g/l
Average mass concentration of all lipids approx. 5 g l–1 .
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Lipoprotein particles transport triacylglycerols
Common structure of lipoprotein particles:
Lipoprotein particles transport triacylglycerols
and cholesterol in body fluids
Common structure of lipoprotein particles:
Hydrophobic core
Superficial layer
(hydrophilic surface)
Hydrophobic core
(hydrophilic surface)
E.g. the diameter of a low-density lipoprotein (LDL) particle is about 30 nm and it
consists of about 50 % cholesterol (both free and esterified), 20 % phospholipids,
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consists of about 50 % cholesterol (both free and esterified), 20 % phospholipids,
20 % apoprotein B-100 and 10 % triacylglycerols.
Plasma lipoproteins
Density
Size
nm
Elpho
mobility
Origin
Protein
%
TG
%
C + CE
%
PL
%
Intestinal 1 – 2
Chylomicrons < 950 100-1000 none
Intestinal
mucosa
1 – 2
B48, A-I > 85 3-7 7
VLDL 950-1010 30-90 pre-β
Liver
(intestine)
< 10
B , C-II, E ~ 60 ~ 15 15VLDL 950-1010 30-90 pre-β (intestine) B100, C-II, E ~ 60 ~ 15 15
IDL 1005-1020 25-30 (VLDL)
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B100, E ~ 30 ~ 40 ~ 20
LDL 1020-1063 20-35 β (IDL)
20
B100
~ 10 ~ 50 20
HDL
Liver
HDL nascent 1125-1210 3.6-4.4
Liver
(intestine)
~ 50
spherical HDL3
HDL2 (CE-rich) 1063-1125 4.4-6.3 α
A-I, A-II
A-I
~ 3
(< 3)
~ 25
(> 25) ~ 25HDL2 (CE-rich)
HDL2 (TG-rich)
1063-1125 4.4-6.3 α A-I
(C, E)
(< 3)
(> 3)
(> 25)
(< 25)
~ 25
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Major plasma lipoproteins and their functions
M
Mean plasma
level Constituent of Function
Major plasma lipoproteins and their functions
Mr
level
mg / l
Constituent of Function
Apo A-I 28 330 1 210
HDL and CM
LCAT activation
HDL and CM
(risk of high II/I ratio)Apo A-II 17 380 370
LCAT inhibition (displaces the
enzyme from lipoprotein)
Apo B100
550 000 950 VLDL, IDL, LDL recognition of LDLApo B100
550 000 950 VLDL, IDL, LDL recognition of LDL
Apo B48
270 000 .. CM recognition of chylomicrons
Apo C-I 6 610 70 VLDL, HDL
LCAT activation,
LPL inhibitionApo C-I 6 610 70 VLDL, HDL LPL inhibition
Apo C-II 8 800 40 HDL, VLDL, CM LPL activation (cofactor)
Apo C-III 8 750 130 VLDL, CM, HDL LPL inhibitionApo C-III 8 750 130 VLDL, CM, HDL LPL inhibition
Apo E2
Apo E
~ 34 000 ~ 50
nascent HDL
HDL →→→→ CM,
recognition of CM, IDL (HDL?)
polymorphic formsApo E3
~ 34 000 ~ 50 HDL →→→→ CM,
VLDL
polymorphic forms
(Apo E4) high levels in coronary heart disease and Alzheimer disease
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Transport of exogenous lipids (dietary fat)
Chylomicrons
apo-B , apo-A-I MUSCLEapo-B48, apo-A-I
apo-C-II, apo-E
(from HDL)
Blood
plasma
MUSCLE
UTILIZATION
LIPOPROTEIN
LIPASE FA
UTILIZATION
by β-oxidation
Thoracic
duct
LIPASE
Apo E receptors
HYDROLYSIS
in lysosomes
REMNANTS
Chylomicrons
ADIPOSE
TISSUE
Apo E receptors
TG
Chylomicrons
Glycerol
FA
RESYNTHESIS
TG
INTESTINE
RESYNTHESIS
of TG (reserve fat)
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Transport of endogenously synthesized lipids
LIPOPROTEIN
LIPASE
VLDL
HDL LIPASE
IDLApo E
receptors
FA
HDL
IDLreceptors
HYDROLYSIS
(and cholesterol)
LDLApo B100
receptors
LIPOPROTEINLIPOPROTEIN
LIPASE
FAApo B100 receptors
HYDROLYSIS in lysosomes
(and supply of cholesterol)
FA
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(and supply of cholesterol)
Function of HDLFunction of HDL
nascent HDL
(discoidal)
nascent HDL
(discoidal)
apo A-I
apo C-II
apo E
(apoC-II and E) CM
VLDL
spherical
HDL2 (TG-rich)
C
LCAT
HDL2 (TG-rich)
HDL3 (C-rich)
CE
TG
picking up cholesterol
from cell membranes
CETP
C
VLDL
CE
CE
TG
LDL IDL
cholesterol ester
C
C
CETP
VLDL
TG
PERIPHERAL TISSUES
cholesterol ester
transfer protein (CETP)
transfers cholesterol esters from
HDL to VLDL in exchange for TG
C
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HDL to VLDL in exchange for TG
Cellular uptake of LDL
Apo B /E receptor-mediated endocytosis of intact LDL:Apo B100/E receptor-mediated endocytosis of intact LDL:
Cholesterol that enters the liver cell this highly specific wayCholesterol that enters the liver cell this highly specific way
inhibits de novo cholesterol synthesis as well as synthesis of
new LDL (apo B100) receptors. (Goldstein and Brown)new LDL (apo B100) receptors. (Goldstein and Brown)
Cholesterol uptake (namely from chemically modified LDL) by scavenger receptors
of macrophages and other types of cells does not regulate intracellular cholesterol
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of macrophages and other types of cells does not regulate intracellular cholesterol
levels, but it may result in formation of foam cells or initiate apoptosis.
Scavenger receptors
internalize modified LDL (oxidized or Tyr-nitroLDL).
While the expression of apo B/E receptor is inhibited by the highWhile the expression of apo B/E receptor is inhibited by the high
intracellular concentration of cholesterol, the expression of the scavenger
receptor remains unregulated (on the contrary, the expression of it is
supposed to be induced).supposed to be induced).
The scavenger receptors class A are present on macrophages,
scavenger receptors class B are on hepatocytes and other cell typesscavenger receptors class B are on hepatocytes and other cell types
(adipocytes, blood platelets, myocytes, endothelial cells, etc.)
It is very interesting that one of the scavenger receptors class B, type I, calledIt is very interesting that one of the scavenger receptors class B, type I, called
membrane protein CD 36 or fatty acid translocase (FAT, identical with the
glycoprotein IV/IIIb on blood platelets) enables the transport of fatty acids, bothglycoprotein IV/IIIb on blood platelets) enables the transport of fatty acids, both
free and esterified cholesterol, and anionic phospholipids across the plasma
membrane through facilitated diffusion.
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