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


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


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


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


• 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


• Heterozygotes

• One gene

• ~ 300 mg/dl LDL in the plasma

• Atherosclerosis before the age of 37


• Homozygotes

• One mutant gene from both parents

• ~ 700 mg/dl LDL in the plasma

• Coronary artery disease in childhood


• 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


• 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


Cholesterol

Bile acids

Synthesis

HMG-CoA

The polymer binds bile salts in the

intestine


Cholesterol

Bile acids

Synthesis

HMG-CoA

Inhibitors of cholesterol synthesis

Metabolism of lipids I V .

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