Download - Metabolism of lipids I V
Metabolism of lipids IV.
Lipid transport process serves four main purposes
Intestine Liver
Adipose tissue
Heart, muscle, kidneys, etc
Dietary fat
Triglicerides
Triglicerides
Cholesterol
Fatty acids
Fatty acidsTriglycerides
Cholesterol
Transport of lipids
Problem: hydrophobic lipids in an aqueous environment
More insoluble lipids (triacylglycerols & cholesterol esters) associated with more polar ones (phospholipids, cholesterol) and protein
HYDROPHILIC LIPOPROTEIN COMPLEX
Transport of lipids
• FFA – free fatty acids– Unesterified long-chain fatty acids
• (less than 5 % of the total)
Lipids of the blood plasma
mg/100 ml (mean) range
Total lipid 570 360-820
Triacyl glycerol 142 80-180
Total phospholipid 215 123-390
Total cholesterol 200 107-320
Free cholesterol 55 26-106
FFA 12 6-16
• Importance:– 50 % of the adult population lipid transport
abnormalities• Risk factors
Lipids of the blood plasma
Metabolism of plasma FFA
ADIPOCYTES
FFA
EXTRAHEPATIC TISSUES LIVER
Triglicerides
FFA / ALBUMIN
HORMONE SENSITIVE LIPASE
OXYDATIONENERGY
SYNTHESIS OFTISSUE LIPIDS
SYNTHESIS OFTISSUE LIPIDS
KETONE BODIES
FFA – FREE FATTY ACIDS
SourceLipolysis of TG in adipose tissue
Lipoprotein lipase during uptake of TG from plasma into tissues
In albumin binding0.1 - 2 meq/mL
6-16 mg/100 ml
FFA – FREE FATTY ACIDS
LevelLow – in fully fed condition
High – in fully fasting state, vigorous exercise in uncontrolled diabetes
Between mealFalls, after eating
Rises, prior to the next meal
FFA – FREE FATTY ACIDS
Removalrapid
In fasting 20-25 % of the energy is supplied by FFA
• can be utilized for the synthesis of lipids in tissues
- FFA taken up by the liver – substrate for ketone body production
- not in the brain!
Lipoproteins
APOPROTEINS
A-I CHYLOMICRON, HDL ACTIVATOR OF LCAT
A-II CHYLOMICRON, HDL
A-III CHYLOMICRON, HDL
B-48 CHYLOMICRON
B-100 LDL, VLDL RECOGNIZED BY LDL-RECEPTORS
C-I VLDL, HDL, CHYLOMICRONS
C-II VLDL, HDL, CHYLOMICRONS ACTIVATOR OF LIPOPROTEIN LIPASE
C-III VLDL, HDL, CHYLOMICRONS INHIBTOR OF VLDL UPTAKE, BY THE LIVER
E VLDL, HDL, CHYLOMICRONS, CHYLOMICRON REMNANTS
RECOGNIZED BY CHYLOMICRON REMNANT RECEPTOR[ALSO BY LDL RECEPTOR – AFFINITY FOR apoE > FOR apoB100]
Fraction Source Density Protein % Lipid Predominant lipid
Chylomicrons Intestine 1-2 98-99 TG
VLDL
(Apo B-100, C, E )
Liver, Intestine 7-10 90-93 TG
IDL
(ApoB-100, E)
VLDL ~11 89 TG, Cholesteryl esters
LDL (B-100) VLDL ~20 79 Pl, Cholesteryl esters
HDL (Apo A; C; E) Liver ~60 ~ 40 PL, cholesterol
FFA Adipose tissue ~99 1
• Patterns with Lipoprotein electrophoresis have been changing by using Bezafibrate SR tablets.
Chylomicron & VLDL
Ch. Clearance from the blood is rapid
Half time > 1 hour
Adipose tissue
Heart
Muscle
On the walls of capillaries
LIPOPROTEIN LIPASEBound to heparan sulfate
Heparin
• Releases LIPORPOTEIN LIPASE into the circulation
• CLEARING OF LIPEMIA
TAKEN UP BY TISSUES
FFA back to the circulation
Chylomicron & VLDL
• PL& apo C-II are cofactors• Chylomicrons & VLDL provide
both– its substrate (TG) and – cofactors CPL, apo C-II)
• Lipoprotein lipase – in heart
• Km for TG low
– In adipose tissue• Km is 10 times greater
– In starvation TG • Heart enzyme remains
saturated
– During lactation / mammary gland
Lipoprotein lipase action
• Loss of 90 % of TG and apo C– Remnant
• Half diameter
• Relatively enriched in cholesterol
– Remnants are taken up by the liver• Receptor: specific for apo E
VLDL
• From the liver– Apo B100 - precursor
of LDL too
– In tissues Lipoprotein lipase
• IDL relatively rich in cholesterol
• Disappears from the blood within 2-6 hours– In liver - it binds to LDL
receptors -affinity for apo E is higher than for B100 - endocytosis by the liver
– Rest in the circulation apo E
• Converted to LDL
HDL
Nascent HDL – secretedby the liver (by the intestine)
PL bilayer + apo C, apo ALecithin-cholesterol acyl-
transferase (LCAT)Cholesterol esters are formed
Move into the hydrophobic interior of PL bilayer pushes bilayer apart until spherical, pseudomicellar HDL is formed
Esterified cholesterols transferred from HDL to chylomicron, VLDL, IDL by cholesterol ester tranfer protein
TRANSPORT OF CHOLESTEROL FROM TISSUES TO THE LIVER
Transport of triglycerides from the intestine to the extrahepatic tissues and the liver. Chylomicrons
Adipose,Muscle,
Heart
TG, from dietsynthesized
Cholesterol, from membranedegradation
Transport of triglycerides from the liver to the extrahepatic tissues. VLDL
`Transport of cholesterol HDL, LDL
LDL
Generally in lipoproteins:In the central core
Nonploar lipidsTriglicerideschoelsteryl ester
Surrounded byphospholipidsunesterified cholesterol apoproteins
LDL receptor: recognize B-100 apoprotein (or apo E)
LDL
Phospholipids, unesterified cholesterol apoproteins
Amphipatic
Nonpolar groups
Interact with lipids in the central core
Polar groups
On the surface Interact with water and ions of theplasma
HDL3HDL2
Lipids Lipids
Apoproteins Apoproteins
E, C
VLDLCh
TG / Che
LCAT
Extrahepatic tissues
Cholesterol
VLDL
TG
Cholesterolesters
PLApoAApoC
Nascent HDL
Uptakeby the liver
LDL receptor
Recognizes Apo B-100Apo E
Mediates the clearance of LDL from the plasma(also of IDL, + recognition factor is ApoE)(VLDL is not binding to B-100 or E receptor, as apo C-III
inhibits binding)
On binding to the receptor endocytic vesicles are formed
LDL receptor
The expression of the LDL receptor is regulated by the need fo the cell for cholesterolDown-regulated – when sufficient cholesterol is
available
Up-regulated – when the cell requires additional cholesterol
LDL receptor
• LDL receptors– Liver– Ovary– Adrenal cortex
• Cholesterol metabolism is controlled by cholesterol released from LDL
Regulation of cholesterol levels in humans
• Plasma cholesterol – in lipoproteins
• Normal cholesterol concentration is– between 3.1 – 5.7 mmol/L (120-220 mg/100 ml)– 65 % is esterified– After an overnight fasting no CHYLOMICRONS
• 70 % of cholesterol in LDL
Regulation of cholesterol levels in humans
Cholesterol free diet 10 % to 25 % decrease in plasma cholesterol concentration
Larger decrease only through inhibition of cholesterol biosynthesis.
Dietary cholesterol restriction is recommended for everyone especially for patients with hypercholesterolemia> 5.2 mmol/L greater tendency to atherosclerosis
Saturated fatty acids plasma cholesterol concentration is increased
Regulation of cholesterol levels in humans
• Reduces the plasma cholesterol concentration by 30 % - 50 %
• Minimum toxicity
Lovastatin, compactin, pravastatin, lovastatin
• The main route of cholesterol metabolism is conversion to bile acids– 0.8 mmol/day of bile acids are lost – (constant level is the body: 15-30 g)
• Bile acid – binding resin– Decreases bile acid reabsorption – increases the loss of cholesterol
– Dietary restriction of cholesterol – Bile acid – binding resin– Cholesterol synthesis – inhibitor
• Cholesterol for bile acid synthesis is provided by LDL
Plasma cholesterol concentration is decreased
Familial hypercholesterolemia
• The absence or deficiency of functional receptors for LDL
• Normal LDL level: 175 mg/dl
• High concentration of LDL-cholesterol in the plasma
• Mutation at a single autosomal locus
Familial hypercholesterolemia
• Heterozygotes
• One gene
• ~ 300 mg/dl LDL in the plasma
• Atherosclerosis before the age of 37
Familial hypercholesterolemia
• Homozygotes
• One mutant gene from both parents
• ~ 700 mg/dl LDL in the plasma
• Coronary artery disease in childhood
Familial hypercholesterolemia
• Homozygotes– Lack of LDL receptors
• Heterozygotes– Half of the normal number– Entry of LDL into liver & other cells is impaired
Increased plasma LDL levelEntry of IDL is also impared more LDL is formedIn Homozygotes: Liver transplantation
Familial hypercholesterolemia
• Therapy for heterozygotes– To stimulate the single normal gene to produce
more LDL receptors– When cholesterol is required in cells the
amount of mRNA for LDL receptor rises & more receptor is synthesized
• High HDL level– protection against coronary heart disease
• Cholesterol – in form of HDL – “good” cholesterol– In form of LDL - harmful
Liver cellsLDL uptake
Cholesterol
Bile acids
Synthesis
HMG-CoA
Liver cellsLDL uptake
Cholesterol
Bile acids
Synthesis
HMG-CoA
The polymer binds bile salts in the
intestine
Liver cellsLDL uptake
Cholesterol
Bile acids
Synthesis
HMG-CoA
Inhibitors of cholesterol synthesis