Metabolism of lipids.

Digestion of lipids.•

An adult ingests about 60 to 150g of lipids per day (90% of which are Triacylglycerols (TG)).

• The human saliva contains no fat-splitting enzymes.

• Therefore in the oral cavity, fats are not digested.

• In adult humans, fats pass through the stomach also essentially unchanged, since lipase, contained in a small amount in the gastric juice of adult humans is not active.

Gastric lipase is not active in adults• The optimal pH for the gastric

lipase lies within the interval of 5,5-7,5.

• In adults the gastric juice pH is about 1,5 (enzyme is not active).

• In addition, lipase can actively hydrolyze only pre-emulsified fats.

• In the stomach, there are no conditions for the appropriate emulsification of fats.

Gastric lipase is active in infants

• The gastric digestion of fats takes place mainly in children, especially infants.

• The gastric pH in infants is about 5, (optimal pH for gastric lipase is 5,5-7,5).

• Fats of milk can be hydrolysed by gastric lipase (milk is emultion).

• In adults the splitting of dietary fats occurs mostly in the upper segments of the small intestine.

• The most potent fat emulsifiers are bile acid salts (supplied to the duodenum in the bile).

• Bile acids are the main end products of cholesterol metabolism and derivatives of cholanic acid.

H3CH3C CH–CH2–CH2–COOH

CH3

Cholanic acid

• Most bile acids are conjugated with glycine or taurine.

The significance of bile acid salts for digestion of lipids :

1) The bile acid salts not only facilitate emulsification, but also stabilize the formed emulsion.

2) Bile acid salts activate pancreatic lipase.

3) Bile acid salts take part in the absorption of fats in the intestine (they form micelles with fat digestion).

Triacylglycerol (TG) degradation.

Pancreatic lipase preferentially removes the FA at carbons 1 and 3.

Absorption of lipids contained in a mixed micelle.

• In the intestinal lumen, long-chained fatty acids and 2-monoglycerides are formed (under the influence of lipase), and they are combined in micelles.

• Micelles are clusters of amphipathic lipids (hydrophobic groups are inside; hydrophilic are outside).

• They are soluble in aqueous solution. These micelles have hydrophobic core (fatty acids, monoglycerides, etc.). It becomes enclosed within a hydrophilic shell composed of bile acids and phospholipids.

• In size, the micelles are smaller by a factor of 100 than the most finely dispersed fat droplets.

• Short and medium chain-length fatty acids do not require the assistance of micelles for absorption by the intestinal mucosa.

Differences in short and long-chain fatty acid absorbtion.

• The short chain fatty acids (with the number of carbon atoms less than 10. Acetic acid (2:0); propionic acid (3:0); butyric acid (4:0); capric acid (10:0).) and glycerol owing to their easy solubility in water, are readily absorbed in the intestine and are supplied to the portal vein blood to be delivered to the liver, escaping ay conversion in the intestinal wall.

• In the intestinal wall from long-chain fatty acids fats are synthesized again specific of the given organism and structurally distinct from the alimentary fat.

TG (exogenous)

emulsification

TG (emulsion)

hydrolysis

DG

2-MG FFA

glycerol

bile acid salts and short-chain FFA

glycerol TG

DG MG FFA

Lungs

Adipose tissue

formation of transport form

thoracic lymphatic

duct

chylomicrons

A

B absorption resynthesis

H2O CO2

blood stream

portal vein

lipase

Bile acid salts

+ bile acid salts

micelles

Pancreas

Liver

Gallbladder

Digestion of phospholipids and cholesterol esters

• As for digestion and absorption of alimentary phosphoglycerides and cholesterol esters, practically all the above listed stages are the same except specific hydrolytic enzymes (phospholipases A1, A2, C, D) and cholesterol esterase (cholesterol, FFA) respectively.

Cholesteryl ester (CE) degradation.

Phospholipid degradation.

TG (exogenous)

emulsification

TG (emulsion)

hydrolysis

DG

2-MG FFA

glycerol

bile acid salts and short-chain FFA

glycerol TG

DG MG FFA

Lungs

Adipose tissue

formation of transport form

thoracic lymphatic

duct

chylomicrons

A

B absorption resynthesis

H2O CO2

blood stream

portal vein

lipase

Bile acid salts

+ bile acid salts

micelles

Pancreas

Liver

Gallbladder

Chylomicron formation.• Triglycerides and phospholipids synthesized in

the epithelial cells of the intestine, as well as cholesterol (possibly, partially esterified) combine with a little of protein to form chylomicrons.

Chylomicron composition.

• Chylomicrons contain 2% protein, 7% phospholipids, 8% cholesterol or its esters, and over 80% triglycerides. The main transported lipid – exogenous TG.

• They are released by exocytosis from intestinal mucosal cells into the intestinal lecteals.

• From the thoracic lymphatic duct, the chylomicrons enter the bloodstream.

Alimentary hyperlipemia.• Already within 1-2 hours after intake of a lipid-

rich diet, the alimentary hyperlipemia is observed in the organism.

• This is a transient physiological state, characterized primarily by an increased concentration of triglycerides in the blood and by the occurrence of chylomicrons in it.

• The alimentary hyperlipemia passes its maximum within 4-6 hours after the intake of fat-rich food.

• In 10-12 hours after the intake of diet, the triglyceride content comes back to the normal level, and chylomicrons are no more observed in the blood.

Lipid malabsorbtion.

• Lipid malabsorbtion(resulting in increased lipid (including the fat-soluble vitamins A, D, E and K, and essential FA) in the feces (that is steatorrhea) can be caused by a number of conditions.

Possible causes of steatorrhea.

1) diseases of liver and gallbladder (inability to synthesize and secrete bile).

2) Diseases of pancreas (inability to secrete pancreatic juice).

3) Defective intestinal mucosal cells (inability to absorb).

Lipoproteins of blood plasma.

• Fat absorbed from the diet and lipids synthesized by the liver and adipose tissue must be transported between the various tissues and organs for utilization and storage.

• Since lipids are insoluble in water, the problem arises of how to transport them in an aqueous environment – the blood plasma.

• This is solved by associating nonpolar lipids (triglycerol and cholesteryl esters) with amphipathic lipids (phospholipids and cholesterol) and proteins to make water-miscible lipoproteins.

Structure of a typical

lipoprotein particle.

• A typical lipoprotein – such as chylomicron or VLDL – consists of a lipid core of mainly nonpolar triacylglycerols and cholesteryl esters surrounded by a single surface layer of amphipathic phospholipid and cholesterol molecules.

• These are oriented so that their polar groups face outward to the aqueous medium, as in the cell membrane.

• 4 major groups of lipoproteins have been identified that are important physiologically and in clinical diagnosis.

These are1) chylomicrons, derived from intestinal

absorption of triacylglycerol; 2) very low density lipoproteins (VLDL, or

pre--lipoproteins), derived from the liver for the export of triacylglycerol;

3) low-density lipoproteins (LDL, or -lipoproteins), representing a final stage in the catabolism of VLDL;

4) high-density lipoproteins (HDL, or -lipoproteins), involved in VLDL and chylomicron metabolism and also in cholesterol transport.

Composition of the

plasma lipoproteins.

• Triacylglycerol is the predominant lipid in chylomicrons and VLDL, whereas cholesterol and phospholipid are the predominant lipids in LDL and HDL, respectively.

• In addition to the use of techniques depending on their density (by ultracentrifuga-tion), lipoproteins may be separated according to their electrophoretic properties into -,- and pre--lipoproteins and may be identified more accurately by means of immunoelectrophoresis.

.

Lipoproteins Electrophoretic fraction

Place of synthesis

The main transported lipid

Chylomicrons1-2%protein;90-1000nm

Origin Intestine Exogenous triacyl-glycerols (from the diet)

VLDL 7-10%protein30-90nm

Pre-β-lipoproteins

Liver (intestine) Endogenous triacyl-glycerols (synthesized within the organism)

LDL 21% protein20-25nm

β-lipoproteins Blood (from VLDL)

Cholesterol (to the tissues)

HDL 33-57% protein10-20 nm

α-lipoproteins Liver (intestine) Cholesterol (from the tissues to the liver and phospholipids)

Albumin-FFA 90% protein

Albumin Blood FFA

• The protein moiety of a lipoprotein is known as an apolipoprotein or apoprotein, constituting nearly 60% of some HDL and as little as 1% of chylomicrons.

• Some apolipoproteins are integral (apo-B) and can not be removed, where as others are free to transfer to other lipoproteins (apo-C)( periferal).

Structure of a typical

lipoprotein particle.

Functions of apolipoproteins.• Apolipoproteins not only give 1) water-solubility to lipids, but they are

necessary for 2) the secretion of lipoproteins by the cells

of the liver and intestine. They are also necessary for

3) the processes of lipoprotein interaction with receptors on the surface of the cells (apo-B100, apo-E).

4) Also several apolipoproteins activate the enzymes, participating in lipoprotein metabolism.

The main types of apolipoproteins.

Apolipoprotein

Lipoprotein Known functions

A Chylomicrons, HDL Coenzyme of LCAT(A-1). Activator of lecithin: cholesterol a acyltransferase .

B Chylomicrons, VLDL, IDL, LDL

Secretion of chylomicrons (B-48); secretion of VLDL; binding of LDL with receptors (B-100); (ligand ror LDL receptor).

C HDL, VLDL, IDL,chylomicrons(from HDL)

Coenzyme of lipoproteid lipase (C-2).

D HDL, VLDL, IDL, chylomicrons (from HDL)

Binding of IDL and remaining particles with receptors.

E HDL Transfer of cholesterol esters.

• In healthy men on an empty stomach blood plasma contains only HDL, LDL and VLDL. In healthy men there is a parallel between cholesterol concentration in plasma and cholesterol amount, included in LDL. The analogous parallel exists between triacylglycerol concentration in plasma and their concentration in VLDL. These conclusions are right for the majority of hyperlipidemia cases.

• There is no apo-B in HDL.• There is no apo-A in VLDL. • Apo-A apo-B apo-B – LDL• Apo-B chylomicrons apo-C VLDL apo-A• Apo-C apo-E apo-C HDL• Apo-E apo-D• apo-E

Metabolism of

chylomicrons

• CM=chylomicron, TG=triacylglycerol, C=cholesterol, CE=cholesterol esters

Metabolism of VLDL and LDL.

Metabolism of HDL.

• PC=phosphatidylcholine, PCAT=Phoshpatidylcholine cholesterol transferase

Role of oxidazed lipoproteins in plaque formation in arterial wall.