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Fatty Liver. Dr. Reham Fares Lecturer of medical biochemistry Faculty of medicine, Fayoum University

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(1)

Fatty Liver

Dr. Reham Fares

Lecturer of medical biochemistry

Faculty of medicine, Fayoum University

(2)

Fatty Liver

ILOs

By the end of this lecture the student should be able to

• Define fatty liver.

• List the different causes of fatty liver.

• Describe the different mechanisms of fatty liver development.

(3)

Fatty Liver

Definition

Normally, the liver contains about 4% of its mass as lipids, mostly as phospholipids.

Extensive accumulation of lipids, mostly as triacyiglycerol is an abnormal condition

known as fatty liver (hepatic steatosis).

(4)

Fatty Liver

It is the most common liver disorder.

The excess fat in the liver causes chronic inflammation which may lead to fibrosis and

impaired liver function.

(5)

Fatty Liver

Causes of fatty liver:

I- Raised levels of FFAs and lipogenesis

II- Defect in the production and

utilization of plasma lipoproteins

(6)

Fatty Liver

Causes of fatty liver:

I- Raised levels of FFAs and lipogenesis

Over mobilization of fats from adipose tissue, as during starvation.

or from hydrolysis of lipoprotein triacyiglycerol by lipoprotein lipase in extrahepatic tissue, as in overfeeding of fats.

This may exceed the capacity of the liver to synthesize VLDL and so fatty liver occurs

(7)

Fatty Liver

Causes of fatty liver:

I- Raised levels of FFAs and lipogenesis

Decreased oxidation of fatty acids due to decrease in pantothenic acid needed for CoA synthesis,

or abnormalities in carnitine shuttle, or

due to alcoholism

(8)

Fatty Liver

Alcoholic fatty liver is caused by alcoholism.

accumulation of fats in the liver is due to

impaired fatty acid oxidation together with increased lipogenesis.

This is due to oxidation of the alcohol leading to increased NADH/NAD ratio and results in

Decrease in fatty acid oxidation

Increase esterification of fatty acids forming triacyiglycerol

(9)

Alcoholic fatty liver

(10)

Fatty Liver

Causes of fatty liver:

I- Raised levels of FFAs and lipogenesis

Over-feeding of carbohydrates exceeding the capacity of the liver to store the excess as glycogen.

Thiamine and biotin stimulate appetite and thus increase food intake and thus

enhance this type of fatty liver

(11)

Fatty Liver

II- Defect in the production and utilization of plasma lipoproteins

*Decreased apoilpoprotein synthesis

*Decreased phospholipids for

lipoprotein synthesis

(12)

Fatty Liver

II- Defect in the production and utilization of plasma lipoproteins

*Decreased apoilpoprotein synthesis,

as in deficiency of essential amino acids, toxic substances such as carbon tetrachioride,

chloroform, phosphorus and arsenic, . all inhibiting synthesis of protein by the liver.

Decreased synthesis of apo B-100 in

abetalipoproteinemia also leads to decrease in VLDL synthesis

(13)

Fatty Liver

II- Defect in the production and utilization of plasma lipoproteins

Decreased phospholipids for lipoprotein synthesis, as in deficiency of essential fatty acids, inositol and choline.

Choline deficiency is caused by dietary deficiency of choline, or in methyl donors as methionine and

glycine betaine, or in vitamin B12 & folic acid

needed for synthesis of methyl groups and may be due to administration of large doses of nicotinic acid or guanidoacetic acid which compete for methyl

groups

(14)

Lipotropic Factors

Definition

:

These are factors which help mobilization of triacyiglycerol from the liver.

They include:

I-Substances essential for protein synthesis 2-Substances essential for phospholipid

synthesis

(15)

Lipotropic Factors

I-Substances essential for protein synthesis, as essential amino acids

including methionine for synthesis of

choline and carnitine

(16)

Lipotropic Factors

2-Substances essential for

phospholipid synthesis as essential fatty acids, inositol and substances

required for choline synthesis (methyl donors as methionine and glycine

betaine and vitamin B12 & folic acid

needed for methylation)

(17)

Role Of Liver In Metabolism

Dr. Reham Fares

Lecturer of medical biochemistry

Faculty of medicine, Fayoum University

(18)

Role Of Liver In Metabolism

ILOs

By the end of this lecture the student should be able to

• List the different roles of the liver in Carbohydrates metabolism.

• List the different roles of the liver in lipids metabolism.

• List the different roles of the liver in protein metabolism.

(19)

I- Role of Liver in Carbohydrate

Metabolism

(20)

I- Role of Liver in Carbohydrate Metabolism

• 1-The liver is the main organ responsible for the regulation of blood glucose.

• 2- It is the main site for metabolism of absorbed fructose and galactose due to presence

d of fructokinase and galactokinase enzymes.

• 3- The Synthesis of different sugars and their derivatives e.g. pentoses, uronic acids and

amino sugars.

(21)

I- Role of Liver in Carbohydrate Metabolism

• 4- Storage of glucose as glycogen.

• 5- Conversion of glucose to fat (lipogenesis).

• 6- Synthesis of glucose from non- carbohydrate compounds

(gluconeogenesis).

(22)

II- Role of Liver in Lipids Metabolism

(23)

II- Role of Liver in Lipids Metabolism

1- The liver produces bile salts

• which is important for digestion and absorption of

fats.

2- Role of liver in metabolism of triacyiglycerol , fatty acids and glycerol

- Uptake of 20% of absorbed FFA and most of fatty acids released from adipose tissue.

(24)

II- Role of Liver in Lipids Metabolism

• - Uptake of most of glycerol.

• - Synthesis of triacyiglycerol from fatty acids released from adipose tissue during

fasting or resulting from hydrolysis of absorbed fat (after a fatty meal).

• The liver is also the main site of synthesis of triacyiglycerol from absorbed sugars.

(25)

II- Role of Liver in Lipids Metabolism

• Synthesis of unsaturated fatty acids,

• oxidation of fatty acids to supply energy

• synthesis of ketone bodies from FFA during starvation.

• Gluconeogenesis: Synthesis of glucose from glycerol released from lipolysis during

fasting.

(26)

II- Role of Liver in Lipids Metabolism

3- Role in phospholipid metabolism

• The liver is the most important organ for the uptake and secretion of phospholipids.

• This occurs through the uptake and secretion of the lipoproteins, HDL, LDL, and

VLDL.

(27)

II- Role of Liver in Lipids Metabolism

4- Role of the liver in the metabolism of plasma lipoproteins

• The liver plays an important role in the metabolism (synthesis, uptake and

degradation) of different plasma lipoproteins

(28)
(29)

II- Role of Liver in Lipids Metabolism

5- Role in steroid metabolism

- The liver is the main site for synthesis of plasma cholesterol.

- The liver converts cholesterol to 7-

dehydrocholesterol (a precursor of Vitamin D3).

- The liver excretes cholesterol through conversion of cholesterol into bile acid and bile salts.

Bile salts are excreted together with cholesterol in bile.

-Detoxification of steroid hormones and partly excreting them in bile.

(30)

III- Role of Liver in Protein Metabolism

(31)

III- Role of Liver in Protein Metabolism

• 1- Synthesis plasma proteins (except γ- globulins).

• 2- The main site for transamination,

deamination, removal of ammonia and urea formation.

• 3- Synthesis of non-essential amino acids.

(32)

III- Role of Liver in Protein Metabolism

• 4- Synthesis of many amino acid derivatives e.g. creatine, heme, purines and

pyrimidines.

• 5- Catabolism of purines and pyrimidines.

• 6- Synthesis of glucose from glucogenic amino acids (gluconeogenesis).

(33)

III- Role of Liver in Protein Metabolism

• 7- Detoxification by conjugation with amino acids.

• 8- Inactivation of many polypeptide or protein hormones e.g. glucagon and

insulin.

(34)

Metabolism of Xenobiotics

Dr. Reham Fares

Lecturer of medical biochemistry

Faculty of medicine, Fayoum University

(35)
(36)
(37)
(38)

Metabolism Of Xenobiotics (Detoxification)

• Xenobiotics include drugs and many compounds that are found in our

environment.

• Detoxification is essentially the

metabolism of the foreign organic

compounds i.e. substances which are not

ordinarily utilized by the organism.

(39)

Metabolism Of Xenobiotics (Detoxification)

• However, it is sometimes also applied to the changes undergone by ordinary metabolites e.g. steroid hormones.

• It usually results in the formation of less toxic more soluble substances which are easily

excreted by the kidneys.

(40)
(41)
(42)

Metabolism Of Xenobiotics (Detoxification)

• In human, detoxification occurs almost exclusively in the liver.

• The reactions of detoxification processes include two main phases:

• Phase One: It includes oxidation (or

hydroxylation), reduction and hydrolysis.

• Phase Two: The product of phase one is

conjugated to other polar compounds to increase their solubility in water and to facilitate their

excretion.

(43)

Metabolism Of Xenobiotics I- Oxidation and Hydroxylation

• Oxidation and hydroxylation

are the most common mechanisms of

detoxification. Hydroxylation is the function of mono-oxygynase or cytocbrome P 450.

1- Primary Alcohols: For example methyl, ethyl and benzyl alcohols are oxidized to the corresponding acids which are formic, acetic and benzoic

respectively.

2- Aromatic Compounds: For example indole, and skatole are oxidized to indoxyl and skatoxyl

(44)
(45)

Metabolism Of Xenobiotics II- Reduction

• This occurs to aromatic nitrocompounds.

• Sometimes both oxidation and reduction may affect the same

compound e.g. p-nitrobenzaldehyde

is converted to p-aminobenzoic acid.

(46)
(47)

Metabolism Of Xenobiotics

II- Reduction

(48)

Metabolism Of Xenobiotics III- Hydrolysis

• Hydrolysis occurs to some drugs, e.g. aspirin (acetylsalicylic acid).

(49)
(50)

Metabolism Of Xenobiotics IV- Conjugation

• Conjugation is a very common mechanism of detoxification.

• Examples for substrates used include the following:

(51)
(52)

Metabolism Of Xenobiotics IV- Conjugation

• 1 - Glucuronic Acid

UDP-Glucuronic acid (glucuronate) is the active donor of glucuronate for

detoxification.

• Glucuronate is used for conjugation with

aromatic acids and phenols as follows:

(53)

Metabolism Of Xenobiotics IV- Conjugation

1 - Glucuronic Acid

(54)

Metabolism Of Xenobiotics IV- Conjugation

2- Active sulfate

• 3-Phosphoadenosme-5’-phosphosulfate (PAPS) is the active donor of sulfate for detoxification.

• Sulfate is conjugated with phenols, alcohols, indoxyl, skatoxyl, and the metabolites of the steroid hormones.

• These ester sulfates are known as ethereal sulfates

(55)
(56)

Metabolism Of Xenobiotics IV- Conjugation

3- Amino Acids a- Cysteine

• Cysteine (in the form of glutathione) is

conjugated with certain aromatic compounds, e.g. bromobenzene and naphthalene, to form mercapturic acids.

• Acetyl-CoA is required for this reaction as follows:

(57)
(58)
(59)

Metabolism Of Xenobiotics IV- Conjugation

3- Amino Acids a- Cysteine

(60)

Metabolism Of Xenobiotics IV- Conjugation

• 3- Amino Acids

b- Glycine and Glutamine

These two amino acids are conjugated with aromatic acids.

• The carboxyl group of the aromatic acid is

connected to the amino group of the amino acid.

• The aromatic acid should first be activated (forms CoA thioester), before condensation with the

amino group of the amino acid, for example:

(61)

Metabolism Of Xenobiotics IV- Conjugation

3- Amino Acids

b- Glycine and Glutamine

References

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