Fatty liver is an abnormal conditioncharacterized by increasing deposition of lipids,mainly T.G. in the liver cells.

When accumulation of lipid becomes chronic,fibrotic changes occur in the cells, whichprogress to cirrhosis and impaired liverfunction.

Fatty Liver

Normal fat content of the liver is about 5% of its

weight and is mainly phospholipids but in fatty

liver it may reach 20-30% and is mainly in the

form of neutral fat.

Fatty Liver

Causes of fatty liver:

1. Increased fat in diet, increased uptake of fats by liver if this exceeds the capacity of thr liver to synthesis VLDL → fatty liver.

2. Over feeding carbohydrate (COH) overload the capacity of the liver to store it as glycogen converts CHO to TG, if this exceed the capacity of the liver to synthesize VLDL fatty liver.

3. Decreased oxidation of FA directs fatty acids to

esterification (TG).

This decreases fatty acid oxidation occurs in the following

condition.

i. Deficiency of pantothenic acid .

ii. Deficiency of carnitine (choline deficiency).

iii. Alcoholism, alcoholic fatty liver is caused by:

A. Decreased FA oxidation as a result of oxidation of

ethanol to acetaldehyde leading to ↑ NADH/NAD ratio.

B. Increased fatty acid synthesis.

Alcohol dehydrogenase

CH3CHO

Acetaldehyde

CH3CH2OH

ethanol

NAD NADH+H+

4. Increased mobilization of fat from adipose tissue to liver cell. This occurs in conditions characterized by decrease carbohydrate utilization e.g. D.M., starvation.

5. Decreased mobilization of fat from liver to blood. TG synthesized in the liver are normally mobilized to blood by VLDL.

Failure to synthesize VLDL may be caused by decreased protein synthesis (apolipoprotein), failure in conjugation or failure in secretory mechanism. Decreased mobilization associated with deficiency of lipotropic factors.

4. Liver poisons e.g. chloroform puromycin and carbon tetrachloride decreased protein synthesis.

Lipotropic Factors:

These are substances that protect against and cure fatty

liver.

They include mainly the substances essential for

phospholipids synthesis.

Phospholipids are easily mobilized from liver and less

liable to deposition in liver cell.

These substances are:

1. Choline lecithin, choline plasmalogen,

sphingomyleine.

2. Methionine required for choline synthesis.

3. Folic acid and B12 transfer of CH3 group

(transmethylation).

4. Inositol phosphatidyl inositol.

4. Essential FA required in position 2 of

phosphoglyceride. Deficiency of essential FA

results from intake of excess cholesterol.

4. Vitamin E & selenium: Protect FFA against

oxidation and peroxide formation.

4. Adequate diet provides high protein,

essential and vitamins.

Role of Adipose Tissue

in Lipid Metabolism

Role of Adipose Tissue in Lipid Metabolism

Adipose tissues carry all metabolic process of any active

tissues.

Calories are stored in it as triglycerides.

The triglycerides of adipose tissue are continually

undergoing hydrolysis (Lipolysis) and reesterification.

Role of Adipose Tissue in Lipid Metabolism

The resultant of these two processes determines the

amount of FFA released from adipose tissue into blood.

The glycerol liberated from the hydrolysis can not be

utilized by fat cell due to deficiency of glycerol kinase

enzyme so it passes to blood.

Thus insulin and a diet rich in carbohydrates

help the reesterification of FAA and decrease

their release into the blood by increasing the

uptake and oxidation of glucose by adipose

tissue.

Fasting glucagon, adrenaline

glucocorticoids and growth hormone have

the opposite effect.

Insulin and a diet rich

in carbohydrates and

fat

Fasting glucagon, adrenaline,

glucocorticoids and growth

hormone have the opposite

effect.

The hydrolysis of triacylglycerol (lipolysis) is underthe control of the enzyme “hormone-sensitivetriacylglycerol lipase”.

This enzyme may exist in one of two forms: Anactive form ”lipase a” which is phosphorylated, andan inactive form “lipase b” which isdephosphorylated.

Metabolism of adipose tissue

cAMP

activated by adrenaline,

noradrenaline glucagons,

ACTH, TSH, MSH

Thyroxine increases the

sensitivity of adenyl cyclase to

hormones by increasing the

membrane receptors.

Growth hormone (GH)

augmenting the synthesis of

adenyl cyclase

Increasing Lipolysis

inhibited by insulin,

prostaglandin E, and

nicotinic acid.

cAMP is hydrolyzed to

5’ – AMP by the enzyme

phosphodiesterase.

activated by adrenaline,

noradrenaline

glucagons, ACTH, TSH,

MSH,thyroxine, growth

H.

inhibited by insulin,

prostaglandin E,

nicotinic acid.

Hormones that Regulate fat Mobilization:

The rate of release of FFA from adipose tissue is affected

by many hormones that influence either rate of

esterification or rate of lipolysis.

Insulin reduces the output of FFA from adipose tissue by:

A. Help reesterification of FA released in adipose tissue.

B. Inhibit activity of hormone- sensitive triglyceride lipase reduce release of FFA and glycerol.

Insulin enhances lipogenesis and synthesis of

triglycerides by:

A. It increases transport of glucose into the cell (e.g. in

adipose tissue) and stimulates glycolysis pyruvic,

glycerol 3 PO4, also stimulates HMP shunt

NADPH+H+.

B. Insulin increase activity of pyruvate dehydrogenase,

acetyl-CoA carboxylase and glycerol-phosphate acyl

transferase, these three enzymes are regulated by

covalent modification i.e. by phosphorylation-

dephosphorylation mechanism.

Several hormones promote lipolysis, these

include epinephrine, norepinephrine,

glucagons, ACTH, MSH, TSH, GH.

facilitating the digestion and absorption of fats by the production of the bile salts.

Plays a central role in the metabolism of various types of TG, steroids, phospholipids, plasma lipoproteins and fat soluble vitamin.

Role of liver in Lipid Metabolism

A. Role in triglyceride and fatty acid metabolism:

Uptake: After meals, the liver takes up about 30% of the free fatty

acids and most glycerol of absorbed fat.

Synthesis: A carbohydrate- rich meal, the liver converts part of the

absorbed sugar into triglycerides.

The liver reesterifies the free fatty acid, released from adipose tissue or resulting from the hydroysis of absorbed fats during fasting and after feeding of fat, into triacylglycerol.

Mobilization:Triacylglycerols synthesized in the liver are mobilized to the blood in the form of VLDL.

Oxidation:The FFA and glycerol are partly oxidized by the liver to supply energy.

Ketogenesis:During starvation, FFA are released from adipose tissue, are taken up by the liver (30%) oxidized to acetyl-CoA which is largely converted to ketonebodies. Ketone bodies go via blood to extra hepatic tissues where they become oxidized to CO2 and H2O.

Desaturation:

Liver is the main site of desaturation of FA.

Gluconeogenesis:

The glycerol released into the blood from adipose

tissue or resulting from the hydrolysis of absorbed

fats is largely to taken up by the liver where it is

converted to glucose. The terminal 3 C of odd

chain FA are also converted to glucose in the liver.

B. Role in phospholipids metabolism:

The liver is the principle organ, which adds and removes phospholipids from the blood plasma.

This function is related to the secretion and uptake of the plasma lipoprotein HDL, LDL and VLDL.

C. Role in steroid metabolism:

The liver is a major site for cholesterol synthesis and important source of plasma cholesterol.

It also removes cholesterol from the blood and converts cholesterol to 7 dehydrocholesterol (for further conversion to vitamin D3) and to bile acids (for secretion into bile).

C. Role in metabolism of plasma lipoproteins

The liver plays a very important role in the metabolism of different types of plasma lipoproteins.