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Lipid Metabolism

Serkan SAYINER, DVM PhD. Assist. Prof.

Near East University, Faculty of Veterinary Medicine, Department of Biochemistry

[email protected]

http://www.biyokimya.vet/

https://neu.edu.tr/akademik/fakulteler/veteriner-fakultesi/?lang=tr

mailto:[email protected]

▪Although carbohydrates and proteins together with some

structural functions such as lipids forming organism's

organic substances are located in cell membranes, their

main function is to become the most important fuel

source after carbohydrates of the organism.

▪The presence of lipids in the nutrients is also important

for fat soluble vitamins and certain unsaturated fatty

acids.

Lipid Metabolism



▪ Lipids form the energy store of the organism. When

weights are taken into account, they give about twice

as many calories as carbohydrates and proteins of the

same weight.• TG gives 9 kcal/g while a carbohydrate or protein gives 4 kcal/g.

▪Despite the limited ability of the body to store

carbohydrates, the oils can be stored in large (like

unlimited) quantities. Nonetheless, the calorie source

preferred by the body is carbohydrates, not lipids.

Lipid Metabolism



▪ Lipids are most often incorporated into the organism in

the form of neutral oils, especially triglycerides (TG).

In addition, cholesterol and other lipids are also taken

into the organism in small quantities.

▪ Lipids carry more carbon, but less oxygen than

carbohydrates and proteins. Therefore, they can be

oxidized more, in other words they can give more

energy.

Lipid Metabolism



▪TG accumulation occurs in the cytoplasm of mammalian

adipose cells.

▪TG droplets come together to form a large globule and

occupy most of the cell volume.

▪Adipose cells are special cells that store, synthesize,

and if necessary, mobilize fuel molecules (free fatty

acids-FFA).

Lipid Metabolism



▪Fatty acids• It is more anhydrous than proteins and carbohydrates

and has higher reduction potentials.

• They are non-polar. They have high hydration

potential.

• They provide more metabolic water (endogen water

synthesis). Especially important in winter sleeping

animals.

Lipid Metabolism



▪The relationship between Total Body Fat, Total Body

Water and lean body mass (LBM) is held within narrow

limits in most normal, adult animals.

▪Total body water may vary depending on age and sex.

▪The body fat ratio is generally around 18% in animals.

Since fat tissue contains less water (per unit wight),

obese animals have relatively less water than lean

animals.

Lipid Metabolism



▪ Total body water is lower in females after puberty than in males.

▪ There is an inverse relationship between total body water and total body fat content.

▪ If the fat content is high, total body water is low.▪ Including intracellular and extracellular.

▪ In reverse; Total body water increases if the fat percentage decreases.

Lipid Metabolism



Source: Engelgink, 2014



▪Energy sources.

▪Structural components of membranes.

▪Protection against physical trauma.

▪Thermal insulators.

▪Metabolic regulators.

▪Digestive aids.

▪Electrical insulators.

Primer Functions of Lipids



Digestion, Absorption

and Transport of

Lipids



▪ Lipolytic argument: After emulsification of the oils,

they are absorbed through triglycerides by breaking

down fatty acids and glycerine. Absorption is completely

with blood.

▪Partition argument: Some fats and oils are absorbed in

the form of mono- and diglycerides. Transit to the tissue

is provided via mesenteric lymph. There is a sharing

between the blood and the lymph in the absorption.

Digestion and Absorption



▪Most of the lipids ingested with foods are triglycerides,

less are phospholipids, free cholesterol, ester

cholesterol and fat soluble vitamins.

▪ Lipid digestion takes place in the form of hydrolytic

cleavage of the ester bonds in the small intestines

(mainly in the jejunum). This hydrolytic cleavage

occurs by the catalytic action of the lipase enzyme.




▪ The lipase secreted by the pancreas is activated by substances such as Ca++ ions, soaps and bile salts.▪ Lipolysis of ingested fat is regulated by two hormones,

cholecystokinin (CCK) and secretin. Both stimulate pancreas.

▪ Because lipase dissolves in water, it shows its effect on lipids on lipid/water boundary surfaces. For this, the boundary surfaces of fats expand and become a microemulsive state due to intestinal peristaltic movements and bile salts. Bile acids have a surface tension reducing effect here.




▪ After hydrolysis of the oils that come into the microemulsion

state, triglycerides are broken down into monoglycerides

and free fatty acids. The lipase enzyme does not affect the

beta-ester linkages of triglycerides.

▪ Cholesterol esters in the intestinal tract are separated into

cholesterol and free fatty acids by the cholesterol

esterase enzyme and phospholipids into the

lysophospholipid and free fatty acids under the influence

of phospholipase.




▪ Enzymes Involved in the Digestion of Dietary Fat


Enzyme Source Substrate Products

Milk Lipase Mammary glands Triglyceride Diglyceride + Fatty Acid

Lingual Lipase Salivary glands Triglyceride Diglyceride + Fatty Acid

Gastric Lipase Stomach/Abomasum Triglyceride Diglyceride + Fatty Acid

Pancreatic Lipase Pancreas Triglyceride and Diglyceride 2-Monoglyceride + Fatty Acid

Cholesterol esterase Pancreas Cholesterol ester Cholesterol + Fatty Acid

Phospholipase A2 Pancreas Phospholipid Lysophospholipid + Fatty Acid



▪These hydrolysis products constitute mixed micelles that all lipids, especially monoglycerides and fatty acid,participate. Depending on the structure of the micel, glycerol, di- and triglycerides may also be present.▪ Lipids are taken up into the mucosal cells in the form of

a micelles. In mucosal cells, fatty acids• Combine with monoglycerides to form triglycerides,

• Combine with free cholesterol to form cholesterol esters,

• Phosphoglycerides also synthesize phospholipids again.

• Short and medium chain fatty acids are sent directly to theliver by portal circulation.




▪All of these synthesis products and free cholesterol

associate with proteins to form chylomicrons.

▪The chylomicrons leave the mucosal cells, first passing

through the tissues, then through the lymphatic

circulation, and finally into the ductus thorasicus. In this

way, the lipids involved in circulation are transported

from there to tissues such as adipose tissue, heart

muscle, liver and lungs.




▪After the chylomicrons carried by the lymph are

involved in the blood circulation, blood plasma get milky

appearance. This is called absorption hyperlipidemia.

Approximately 5-6 hours after ingestion, absorption

hyperlipemia reaches the highest level. After about 10-

12 hours, the plasma clears and returns to normal.

▪The clarification of the plasma occurs when

chylomicrons are enter to the cells. Plasma clearing

factor is needed for the entrance of chylomicrons into

the cells.




▪The chylomicrons are broken up into the building blocksafter they enter tissue cells.

▪Thus, the fatty acids and other lipids which are released are used in different forms according to the tissues which they are broken.

▪ For example, adipose tissue is stored again by forming triglycerides, while in the heart, it is oxidized to produce energy.




▪ Cholesterol transported to the liver is metabolized here.

▪ Cholesterol is mixed with the cholesterol that is synthesized endogenously by the liver.

▪ The total amount of cholesterol in the organism is under strict control by the liver.

▪ If cholesterol absorption increases, the synthesis slows down and bile and cholesterol excration are accelerated. Inversely, synthesis increases, if uptake decreases.




▪The fact that the digestive system of ruminants is

different from other animals also affects lipid digestion.

As the fat content of ruminants is very low, small

amounts of triglycerides are found in the intestines.

▪These are also hydrolyzed by intestinal microflora. Then

they are saturated with hydrogen, resulting in more

saturated free fatty acids in the intestines of ruminants.

Digestion and Absorption in Ruminants



▪The lipid group that holds the most important place in

the lipid metabolism of ruminants is the volatile fatty

acids.

▪Carbohydrates, which are mainly included in the

ruminant diet, are absorbed as volatile fatty acids

(acetic acid, propionic acid and butyric acid), which

are obtained as a result of fermentation of cellulasein

the digestive tract.




▪Of these volatile fatty acids used by the liver,

propionic acid is most commonly used in

carbohydrate metabolism.

▪Acetic and butyric acids are also used in the

synthesis of fatty acids.




▪ Since lipids are not water-soluble substances, they can

only be transported by blood if they become soluble in

water.

▪ For this, lipids bind to specific proteins to form

lipoproteins and become soluble state.

▪Free fatty acids (FFA) are transported by binding to

albumin. Hypoalbuminemia disturb transort of FFA.

Transport of Lipids



▪Fatty substances in the blood are found in

three different forms.

1. In the form of particles called chylomicrons

2. Invisible fatty fragments

3. In the esterified state bound to albumin

Transport of Lipids



▪The excretion of abnormal quantities of fat with the faeces owing to reduced absorption of fat by the intestine is called steatorrhea.▪The most common causes of steatorrhea are bile acid

insufficiency, pancreatic enzyme deficiency, chylomicron synthesis problem, and obstruction of lymphatic circulation.▪As a result of lipid malabsorption, deficiency of soluble

vitamins in fat, calorie deficiency, diarrhea and steatorrhea are seen.

Lipid Digestion and Absorption Abnormalitie



Blood and Body

Lipids



▪Blood lipids mainly consist of triglycerides,

lipoproteins, phospholipids, cholesterol and

free fatty acids.

▪A normal blood plasma covers an average of 500-

600 mg/dl total lipid on fasting state. Total lipid

limits may vary from 350 to 800 mg/dl.

Blood Lipids



▪Total lipids consist of

•1/4 triglycerides,

•1/3 to total cholesterol.oThis cholesterol is also present in the form of

2/3 esterified with fatty acids, 1/3 free

cholesterol.

Blood Lipids



▪After meals, the blood will take a milky appearance.

This is due to chylomicrons.

▪Chylomicron consists of • 83% triglycerides,

• 2% protein,

• 7% phosphoglyceride,

• 8% cholesterol (2% free, 6% ester cholesterol).

Blood Lipids



▪ The presence in the blood of an abnormally high concentration of lipid is called lipemia. Lipids are transported in the form of lipoproteins.

▪ Low-density lipoprotein (LDL) consists of more of triglyceride and cholesterol than protein fraction. This lipoprotein is of interest to vascular stiffness. It is also called bad cholesterol.

▪ High-density lipoproteins (HDL) are called lipoproteins where the protein fraction is more abundant. It is referred as good cholesterol.

Blood Lipids



▪Animal's body weight inculed 10% lipids.

▪Lipids are involved in connective tissue, adipose

tissue and cytoplasm of cells.

▪The storage fats of ruminants are separated from

the others by high-stearic acid, unsaturated

fatty acids and branched fatty acids.

Body Lipids



▪ Sphingomyelin Lung and brain tissue

▪Plasmalogens Muscle and brain tissue

▪Glycolipids Nerve

▪Cerebrosides Gangliocytes in the nerve tissue

▪Cholesterol In the brain, liver and plasma

Body Lipids



▪Triglycerides: Adipose tissue and liver

▪Unsaturated fatty acids: Most in the liver

▪Phospholipids: In all tissues other than adipose tissue

▪ Lecithin, cephalin: Almost all tissues

▪ Inositol phospholipids: Liver, heart and brain

Body Lipids



Summary of Lipid Metabolism

Pathways of Lipids in

the Liver



▪Fatty acids are either oxidized or activated to synthesize Acetyl CoA and ATP.

▪Acetyl CoA's are oxidized by oxidative phosphorylation in the citric acid cycle to form ATP.

▪The fatty acids in the liver are the major oxidative fat fuels.

Oxidation to CO2 and ATP production



▪ In the liver, ketone bodies are formed from Acetyl CoA.

▪The resulting acetoacetate and β-hydroxybutyric acids are used for energy production in peripheral tissues.

▪These substances are not used by the liver for energy supply.

Utilization of Ketone Bodies



▪ Some Acetyl CoA's, which are obtained via oxidation of fatty acids, are used for cholesterol synthesis.

▪ The source of bile acids, which are essential for the absorption and digestion of lipids, is cholesterol.• In most cases, cholic acid and chenodeoxycholic acid are primary

bile acids.

• After synthesis, it is conjugated with amino acids (taurine) and released into bile.

• Bile acids are stored in the bile. After the consumption of food is poured into the small intestines.

• Oils and fats are essential for the digestion and absorption of vitamins.

Bile Acids and Cholesterol



▪Fatty acids are stored as triacylglycerols.

▪They are used as a starting material for the

synthesis of lipid moieties of lipid-carrying

plasma lipoproteins.

Synthesis of Plasma Proteins



▪Free fatty acids are transported to the

skeletal and cardiac muscles by binding to

serum albumin and are used as fuel source.

Shaping of Free Fat Acids



Fatty Acid Oxidation



▪The triglycerides that are brought to liver within the

chylomicrons, are broken down into glycerol and fatty

acids.

▪Glycerol is treated as discussed in carbohydrate

metabolism. Fatty acids are oxidized which is called β-

oxidation.




▪A common molecule is involved in the synthesis and

oxidation of fatty acids.• Fatty acids are synthesized from Acetyl-CoA.

• Fatty acids are oxidized to Acetyl-CoA.

▪Oxidation of fatty acids occurs mainly in

mitochondria.• Synthesis occurs in the cytoplasm.




▪ Fatty acids are important energy sources for muscle, kidney and liver tissue.

▪Free fatty acid (FFA) expression generally refers to non-esterified long-chain fatty acids (LCFA). This expression is also used as non-esterified fatty acid (NEFA).

▪ LCFAs are transported linked to serum albumin. SCFAsand MCFAs are freely transportable because they are more soluble.




▪ Short-Chain FA• Acetic acid (C2:O)

• Propionic acid (C3:0)

• Butyric acid (C4:0)

• Valeric acid (C5:0)

▪Medium-Chain FA• Caproic acid(C6:0)

• Caprylic acid(C8:0)

• Capric acid(C10:0)

• Lauryl acid(C12:0)


▪ Long-Chain FA• Miristoleic acid (C14: 1)

• Palmitoleic acid (C16: 1)

• Oleic acid (C18: 1)

• Linoleic acid (18C: 2)

• Linolenic acid (18C: 3)

• Arachidonic acid (20C: 4)

• Palmitic acid (C16: 0)

• Miristic acid (C14: 0)

• Stearic acid (C18: 0)

• Arachidic acid (C20: 0)



▪ Fatty acids are activated before further metabolize by

using 2 moles of ATP. This is similar to glucose

activation (glucose to glucose-6-P). The fatty acyl-CoA

is obtained and the reactions proceed on this active

intermediate.

▪ It is the only step in fatty acid catabolism that ATP is

used and it’s irreversible. The enzyme responsible for

this activation is Acyl-CoA synthetase.• It is located in endoplasmic reticulum, inner and outer mitochondrial membrane.

• There are different types and each is specific to fatty acids with different chain lengths.

• All are dependent on pantothenic acid.




▪Carnitine• It is synthesized from lysine and methionine in the liver and

kidney. Spread throughout all tissues; Especially in

mitochondrial membranes of muscle tissue.

• MCFA activation and oxidation in mitochondria are

carnitine-independent. But LCFA-CoA’s are not passed

through inner mitochondrial membrane without carnitine,

thus not oxidized.




▪ Carnitine

• Carnitine palmitoyltransferase I (CPT-1), an enzyme

present in the outer mitochondrial membrane, converts

long-chain fatty acyl-CoA units to acylcarnitine.

• This compound next gains access to the inner

mitochondrial matrix and β-oxidation system of enzymes

through the action of carnitine-acylcarnitine translocase

(CAT), an enzyme which acts as an inner mitochondrial

membrane carnitine exchange transporter.




▪Carnitine• While acylcarnitine is transported in, one molecule of

carnitine is transported out.

• Acylcarnitine then reacts with CoA, catalyzed by carnitine palmitoyltransferase II (CPT-2), located on the inside of the inner mitochondrial membrane. Fatty acyl-CoA is reformed in the mitochondrial matrix, and carnitine is released.

• Another enzyme, carnitine acetyltransferase, is thought to facilitate transport of acetyl groups through certain mitochondrial membranes.




Carnitine

Shuttle

System




▪Mitochondrial β-oxidation of LCFAs is a cyclic process

and involves 4 enzymes. When each cycle is complete,

the acetyl-CoA is removed from the carboxyl end of the

fatty acid.

▪ In addition, 1 mole of FADH2 and 1 mole of NADH are

obtained. In these, 5 ATP is obtained by oxidative

phosphorylation.

Mitochondrial β-Oxidation



▪Palmitic Acid (C16:0)

• The number of cycles are 7 and a total of 7 x 5 = 35 ATP

are synthesized.

• A total of 8 Acetyl-CoA are formed.

• When acetyl-CoA enters TCA, 8 x 12 = 96 ATP are

produced.

• In total 1 mole palmitate gives 131 mole total ATP.

• Two moles of ATP are used in the activation of fatty acid.

• Thus, the net energy obtained from 1 mole palmitate is

129 moles ATP.




▪ There are three isozymes of fatty acyl-CoAdehydrogenase, the enzyme that catalyzes the first step in β-oxidation: long-chain (LCAD), medium-chain (MCAD), and short-chain acyl-CoA dehydrogenase (SCAD), that work on C14-C18, C6-C12, and C4 FAs, respectively. The completeoxidation of LCFAs requires all three isozymes, with MCAD and SCAD becoming preferred isozymes as the FA becomesprogressively shorter.

▪ Each oxidation cycle of long chain, double number of C and saturated fatty acids occurs in 4 steps.




1. Oxidation (Dehydrogenation-I)• Activated fatty acid is dehydrogenated from α and β-Cs by

acyl-CoA dehydrogenases.

• Double bonds are formed by losing 2 H at these points. The result is Enoyl-CoA.

• Eventually, the FAD takes up Hs and 1 mole of FADH2 is formed. It enters to the respiratory chain and 2 ATPs are synthesized.

• The reaction is irreversible.o In the fatty acid synthesis, NADP is involved in the recycling by

reductase enzyme.




2. Hydration• In this step, 1 mole of H2O is

attached to the double bond in

the desaturation event.

• The result is β-hydroxyacyl-

CoA.

• This reaction is catalyzed by

enoyl-CoA hydratase

(crotonase) enzyme.





3. Oxidation (Dehydrogenation-II)• The OH group of β-hydroxyacyl-CoA, which occurs in the

previous step, is oxidized to a keto group and β-ketoacyl-

CoA occurs.

• The reaction is catalyzed by β-hydroxyacyl dehydrogenase

enzyme.

• The hydrogens are taken by NAD+ and consequently 3 ATP

are synthesized by entering to the respiratory chain.




4. Thiolytic Degradation (Thiolysis)• In this final step, β-ketoacyl-KoA reacts with a new KoA.SH

leaving 1 mol of acetyl-CoA.

• The backward 2 C residue is the CoA derivative of the fatty acid (shortened chain fatty Acyl-CoA), that is activated form.

• The reaction is catalyzed by thiolase enzyme catalysts.

▪ Then the cycle starts again from Dehydrogenation I which is step 1. Repeatedly every cycle, the fatty acid chain is shortened 2 Cs and eventually cleaved completely into acetyl-CoA.




• The obtained acetyl-CoAs can be used in the synthesis of the fatty acids and in the synthesis of the steroids, as well as in the TCA cycle, for energy production.




▪ Fatty acids with an odd number of carbon atoms are oxidized by the pathway of β-oxidation until the final 3-carbon propionyl-CoA residue remains. This compound is then converted to succinyl-CoA, a constituent of thetricarboxylic acid (TCA) cycle.

▪ Unsaturated fatty acids (UFA) are similarly oxidized by β-oxidation until the unsaturation point (double bond) is encountered. Afterwards, oxidation is continued by making them compatible with some reactions. (cis trans, epimerization of D L forms).




▪A secondary form of β-oxidation occurs in

peroxisomes of the liver and kidney. It differs from its

mitochondrial counterpart in several respects.• It is quantitatively less important.

• Entry of fatty acyl-CoA does not require the carnitine shuttle,

for peroxisomes lack carnitine palmitoyltransferase I (CPT-I).

• Oxidation is catalyzed by different enzymes, such as oxidases

that require a high oxygen tension, and produce H2O2 as a

byproduct.

• Catalase is a prevalent enzyme in peroxisomes.

Peroxisomal β-Oxidation



▪Oxidation of very long chain fatty acids (e.g. C20-C22,

Arachidic acid, Behenic acid) is particularly difficult to

achieve by mitochondria, and peroxisomal β-oxidation is

important at this point.

▪ Peroxisomal enzymes are triggered by the consumption

of foods, especially those with very high fat content.




▪ ince oxidation is uncoupled from phosphorylation in

peroxisomes (like in brown fat tissue), these organelles

function in thermoregulation as well as in disposal of

potentially harmful lipid peroxides from very LCFAs.

▪Another function of peroxisomes is to shorten the side

chain of cholesterol in bile acid formation.

▪ Zellweger Sendromu




Fatty Acid Biosynthesis



▪The synthesis of fatty acids occurs in a different way

than the oxidation of fatty acids.

▪ Fatty acids are synthesized from Acetyl CoA.

▪ Fatty acid biosynthetic system has been found in several

different organs and tissues, including liver, kidney,

brain, lung, mammary, and adipose tissue.• Major tissues are liver and adipose tissue.




▪ In eukaryotic organisms, the oxidation of fatty acids

occurs in mitochondria, where as their synthesis

occurs in cytosol (up to 16 C palmitate).

▪ In the synthesis of longer chain fatty acids and the

synthesis of unsaturated fatty acids (double bonds),

mitochondria and smooth endoplasmic reticulum are

involved.




8 Acetyl CoA + 7 ATP + 14 NADPH

Palmitate + 7 ADP + 7 Pi + 14 NADP+ + 8 CoA.SH + 6 H2O




▪The active thioesters in fatty acid oxidation are the CoA

derivatives. Whereas acyl carriers in fatty acid synthesis

are coupled to acyl carrier protein (ACP) as thioesters.

▪The oxidation reaction are catalyzed by the different

enzymes, whereas in mammals most of the biosynthesis

reactions are catalyzed by a multifunctional protein

with two polypeptide chains.




▪ Synthesis and oxidation events have 2 carbon steps.

However, the oxidation event is terminated by two

carbon units of acetyl CoA.

▪However, the synthesis requires malonyl-KoA, a three

carbon substrate that transfers two carbons to

elongated chain. CO2 is released in this case. As a result,

there is a need for NADPH in the reduction instead of

NAD. It is used in the oxidation.




▪ Fatty acid synthesis in eukaryotes occurs in 3 steps.1. In the first step, mitochondrial acetyl-CoA is transported to

the cytosol.

2. In the second step, malonyl-CoA is synthesized via

carboxylation of acetyl CoA. o This step is also referred as the chain elongation reaction because

the fatty acid chain is elongated. The carboxylation of acetyl CoA is

regulated by the step of fatty acid synthesis.

3. Finally, the true integrity of the fatty acid chain is provided

by fatty acid synthase.




1. CITRATE TRANSPORT SYSTEM• It is a system that provides acetyl CoA to cytoplasm.

• The acetyl CoAs required for the synthesis of fatty acids in the

cytosol of eukaryotic organisms are obtained from the

mitochondria where they are produced.

• In the absence of hunger, fatty acids are synthesized from

acetyl CoA produced from carbohydrate metabolism.

• The removal of acetyl CoA from the mitochondria is carried

out by the citrate transport system.




• In the first step, the mitochondrial Acetyl CoA is coupled with

oxalocetate in a reaction carried out by the citrate synthase

enzyme. This reaction is also the first step of TCA.

• In the other step, the citrate is transported freely out of the

mitochondria via citric acid.

• Citrate is separated into oxalocetate and acetyl KoA by a

reaction catalyzed by citrate lyase and ATP.




• Mitochondrial malate dehydrogenase is an isoenzyme of

cytosolic malate dehydrogenase, converting NADH to NAD+,

and oxalacetate → malate.

• The other reaction is formed by the reduction of NADP to

NADPH and the malate is decarboxylated in a reaction

catalyzed by the malic enzyme.

• In this reaction, the citrate transport system not only transfers

acetyl CoA from mitochondria to the cytosol, but also

produces cytosolic NADPH. NADPHs are needed in the next

steps of fatty acid synthesis.




• The newly formed pyruvate is shuttled to mitochondria by

pyruvate transcholase.

• This pyruvate is then carboxylated to form oxaloacetate with

an ATP required reaction or converted to acetyl CoA via the

pyruvate dehydrogenase complex, thereby completing the

reaction.




2. MALONYL CoA SYNTHESIS• The second step in fatty acid synthesis is a reaction catalyzed

by the biotin-dependent enzyme Acetyl-CoA carboxylase to form malonyl CoA in the cytosol by carboxylation of Acetyl CoA. o It is rate-limiting enzyme and activated allosteric by citrate and

isocitrate.

o Palmitoyl-CoA inhibits by negative feedback.

o Insulin activates. Glucagon and epinephrine inhibits.

• The carboxylation of acetyl CoA takes place in two steps.1. Carboxybiotin is formed by activation of ATP-dependent HCO3.

2. The first reaction follows transfer of the activated carbon dioxide to Acetyl CoA.




3. FINAL STEP OF FATTY ACID SYNTHESIS• The synthesis of fatty acids is carried out from these groups

after transfer of Acetyl CoA and Malonyl CoA to the prosthetic group phosphopantetheine. The same group is also found in Coenzyme A.

• In mammals, a single polypeptide chain contains all catalytic activities. The prosthetic group is incorporated into the multifunctional protein and the active form is less common.

• There are 5 reactions in the last step.




1. Initiation Reaction• Acetyl CoA and malonyl CoA are esterified by transfer to ACP

(acyl carrier protein).

2. Condensation Reaction• Ketoacyl ACP synthetase takes an acetyl group from acetyl

ACP and releases ACP_SH1. The ketoacyl synthetase thentransfers the acyl group to the malonyl ACP and formsacetoacetyl-S-ACP by providing CO2 from the subsequentsubstrates. The synthesis of malonyl CoA requires ATP-dependent carboxylation.




3. Reduction Reaction• The ketone of acetoacetyl-ACP is converted to an alcohol, thus

forming a β-hydroxybutyryl-S-ACP in a NADPH-dependent

reaction catalyzed by ketoacyl ACP reductase.

4. Dehydration Reaction• A dehydratase enzyme allows the formation of a double bond

with the separation of the water. Thus crotonyl-S-ACP forms.




5. Reduction Reaction• The dehydration product transbutenoyl-ACP is reduced to form an

acyl-ACP, that is butyryl-S-ACP, of 4 carbon lengths in a reaction catalyzed by NADPH-dependent enoyl-ACP reductase.

▪ The synthesis process continues with the condensation reaction, with acetyl-ACP replacing the acyl-ACPs and forming a new malonyl CoA into each cycle.

▪ The synthesis process continues until the 16 carbon palmitoyl group is formed.

▪ Animals can usually synthesize all fatty acids except for essential fatty acids.




▪Cytoplasmic System• In this system, Acetyl CoA 's combine with each other to bring

long-chain fatty acids.

• The substances required for synthesis are ATP, CO2, Mn+2,

NADPH.

• This system is also called palmitate synthesizing system.

• In the cytoplasmic system, fatty acids are regenerated.

Fatty Acid Elongation Beyond Palmitate



▪Mitochondrial System• Acetyl CoA 's are added by the action of an oil, acide,

nicotinamid coenzymes, and medium and long chain fatty acids are synthesized.

• In this system chain elongation reactions are dominant.




▪Microsomal System• Formation of unsaturated fatty acids carrying more than one

double bond and elongation of active derivatives of fatty acids.

• NADPH and malonyl CoA are used for this purpose.

• The microsomal system also includes the chain elongationreaction.

• Acetyl CoAs required for the synthesis of fatty acids occur when the acetyl CoA in the mitochondrion is converted to citrate than pass through the mitochondrial membranes and the citrate is converted back to acetyl CoA in the cytoplasm.




Fatty Acid Synthesis and NADPH Production




Triglycerides and

Glycerophospholipids



▪The cytoplasmic biosynthesis of triglyceride and

glycerophospholipid begins with glycerol 3-phosphate

formation.

▪Most fatty acids are found in the cell in the form of

triacylglycerol or glycerophospholipid and in ester form.

▪ Phospholipids are classified according to their metabolic

origin; acidic (anionic) phospholipids, such as

phosphatidylinositol, neutral phospholipids (zwitterion)

such as phosphatidylethanolamine.

Triglycerides and Glycerophospholipids



▪ Neutral phospholipids, phosphatidylcholine and

phosphatidylethanolamine, are synthesized in a common

pathway.

1. First, dihydroxyacetone phosphate (from glycolysis) is

reduced to glycerol-3-phosphate.This reaction is catalyzed

by glycerol-3-phosphate dehydrogenase.

2. Glycerol-3-phosphate then serves as a backbone for the

acylation reaction catalyzed by two acyltransferases with

fatty acid acyl CoA molecules forming the source of acyl

groups.




3. The first acyl transferase, which is preferred for fatty acid

acyl molecules with saturated acyl chains, catalyzes

esterification at the 1st carbon of glycerol-3-phosphate.

4. The second acyltransferase, which has more affinity for the

unsaturated ones, catalyzes the esterification of the

monoacylglycerol-3-phosphate in the 2nd carbon.

5. The terminated molecule is phosphatidic acid. This term

refers to a group of molecules that are capable of binding to

acyl groups.




▪ In the formation of neutral lipids, the other step is the

dephosphorylation of phosphatidate, which is

catalyzed by phosphatidate phosphatase.

▪The product of this reaction is 1,2-diacylglycerol, which

is converted to triacylglycerol or phosphatidate is

reacted with a CTP derive substrates, CDP-choline or

CDP ethanolamine, to form CDP-diacylglycerol

▪Two phospholipids, phosphatidylcholine or

phosphatidylethanolamine, are formed in turn.




▪ Phosphatidylcholine synthesis requires CDP (cytidine diphosphate)-choline.

▪ It is catalyzed by the choline kinase and is formed by the phosphorylation of the choline.

▪ The diacylglycerol reaction with CDP-choline completes the synthesis of phosphatidylcholine. A parallel series of reactions is to form phosphatidylethanolamine with different kinase and transferase enzymes required for the same stage.




Eicosanoids



▪ Eicosanoids are arachidonic acid derivative molecules.If the diet contains enough linoleic acid, the arachidonic acid can be synthesized in a certain amount.

▪The arachidonic acid in the cell forms the source of many products called eicosanoids. A group of long chain unsaturated fatty acids act as metabolic regulators.

▪ In general, the regulatory molecules of eicosanoids are synthesized via two different pathway.

Eicosanoids



▪The first class is the cyclization of the arachidonate,

which is catalyzed by cyclooxygenase.

▪The compounds of this group are called prostaglandins

(PG), prostacyclin and thromboxane (TX) and are local

regulators.

Eicosanoids



▪ Eicosanoides,• Provide the sensitivity of pain and swelling.

• Are also referred as tissue hormones. Their release affects

neighboring cells (paracrine and/or autocrine effects). o Aspirin blocks these effects of eicosonoids because salicylic acid, the

active ingredient of aspirin, irreversibly inhibits cyclooxygenase by

transferring an acetyl group to the active site of the enzyme. Prevents

aspirin eicosonoids from forming by blocking cyclooxygenase activity.

Eicosanoids



▪The second class of eicosonoids is the products of

reactions catalyzed by the lipoxygenase enzyme.

▪ Lipoxygenase catalyzes the first step in the synthesis of

leukotriene A4.

▪The subsequent reaction allows the formation of other

leukotrienes, which are anaphylactic and affect the

immune system.

Eicosanoids



Synthesis of Acidic

Phospholipids and

Ether Lipids



▪Acidic phospholipids have a negative charge because

acid groups are usually phosphoric acid and dissociate at

physiological pH.

▪The first source for acidic phospholipids is the

phosphotidate which is formed by the way that

phosphatidates are synthesized.

Synthesis of Acidic Phospholipids and Ether Lipids



▪The first step to form CDP-diacylglycerol is the

incorporation of phosphatidate and CTP.

▪ Second step, • In E. coli; It is the formation of phosphatidylserine by the

introduction of CDP-diacylglyceride and the release of CMP.

Enzyme; phosphatidylserine synthetase.

• In both prokaryotes and eukaryotes, phosphatidylinositol is

formed from CDP-diacylglycerol by the induction of inositol

and the release of CMP.

Synthesis of Acidic Phospholipids and Ether Lipids



▪ Ether lipids are synthesized from dihydroxyacetone-P

and have ether-type bonding where ester bonding

occurs.

▪ Such lipids are derived from glycerol-3-phosphattenone

dihydroxyacetone-P, which is the source of most

phospholipids.

Synthesis of Ether Lipids



▪ First, an acyl group of the fatty acid acyl group is

esterified by bonding to the dihydroxyacetone-P at 1.

carbon. The enzyme that performs this reaction is

dihydroxyacetone-P acyl transferase. As a result, 1-acyl-

dihydroxyacetone-P and 1-alkyl-

dihydroxyacetonephosphate are formed.

▪The 1-alkyl dihydroxyacetone-P ketone group is then

reduced to 1-alkylglycero-3-P by NADPH.




▪ Following reduction, esterification takes place on the

second carbon of the glycerol residue and forms 1-alkyl-

2-acylglycerol-3-P.

▪Dephosphorylation in the subsequent reactions and

transfer of the choline group are as previously

demonstrated in the synthesis of neutral lipids.




▪A class of ether lipids, termed plasmalogens, contains

one vinyl ether linkage in the first carbon of the

glycerol backbone.

▪The physiological functions of plasmalogens and other

ether lipids are not usually obvious. However, the role of

the ether lipid, known as the platelet-activating factor,

is known.




▪The ether lipid molecule, which contains a palmitoyl

group at the 1st carbon of the glycerol skeleton and an

acetyl group at the 2nd carbon, acts as the platelet

activator factor in the clustering of the platelets during

blood clotting.

▪Thrombocyte activator factor has a strong effect and

amounts of 0.1 nM are quite effective.




Sphingolipids



▪ Sphingolipids, are formed from palmitoyl CoA and

serine.

▪ Sphingolipids form a class of membrane lipids that

contain structurally sphingosines in their skeletons.

▪There is sphingosine here, similar to the glycerol in the

phosphoglyceride.

Sphingolipids



▪ In the first phase of the biosynthesis pathway of sphingolipids, serine is combined with palmitoyl CoA and3-ketosphinganine is formed.▪The reduction of 3-ketosfinganine by NADPH-dependent

3-ketosphinganine reductase results in a sphinganine.▪Thereafter, desaturation takes place with a reaction

catalyzed by sphinganine dehydrogenase which contains flavine.▪ Sphinganine dehydrogenase are located inside the

cytoplasmic membrane in the way that the active surface comes to the cytosol.

Sphingolipids



▪ The ceramide formed in the acetylation of sphingosine (sphingosine acyltransferase) is then changed to enter the reaction to form a cerebroside with phosphatidylcholine and sphingomyelin or UDP-sugar.

▪ The sugar lipid composition having a more complex structure can be formed by the reaction which allows the addition of the sugar portion (half) of UDP sugars.

▪ The last molecules formed are the gangliosides. Gangliosides form part of the external charge of plasma lipids, such as antigen recognition in mammals and most sugar lipids.

Sphingolipids



Sphingosine acyltransferase




Cholesterol

Biosynthesis



▪Cholesterol is synthesized from the cytosolic acetyl-

CoAs.

▪Most animal cells have cholesterol, but the site of

synthesis is liver.

▪Cholesterol, which is synthesized in the liver and taken

up with food, is transfered to body cells (peripheral

tissues) by lipoproteins.

Cholesterol Biosynthesis



▪ In the synthesis of cholesterol, the understanding of the acetyl CoA's incorporation into synthesis has been elucidated by radioisotope assays.

▪Another part apparently is squalene, which has a linear 30 carbon and is an intermediate in cholesterol biosynthesis.

▪While the squalene is forming, the 5-carbon isoprene units combine (that is terpene).




▪Cholesterol biosynthesis occurs in 4 steps.

1. Formation of Mevalonate (5 C)

2. Conversion of mevalonate to Isoprenoids (5 C)

3. Condensation of isoprenoids to squalene (30 C)

4. Conversion of Squalene to Cholesterol (27 C)




▪Cholesterol is synthesized from acetyl CoA which istransported from the mitochondria by the citrate transport system.

▪These two major lipid biosynthetic pathways are metabolic pathways, as cytosolic acetyl-CoA is also used for the synthesis of fatty acids.

▪The first step in the synthesis of cholesterol begins with the formation of hydroxymethylglutaryl-CoA (HMG-CoA) by combining 3 molecules of acetyl CoA.

Mevalonat Formation



▪The HMG-CoA reductase enzyme, which catalyzes the mevalonate reduction of HMG-CoA, is a rate-limiting enzyme in the cholesterol synthesis pathway.

▪ It is inactivated by phosphorylation and is interconvertible.

▪ In addition, the amount of enzyme in the cell is tried to be kept regularly.

Mevalonat Formation



▪ Insulin enhances HMG-CoA reductase activity, while glucagon has an adverse effect.

▪ In addition, the long-chain acetyl CoA molecules inhibit HMG-CoA reductase by acting directly on the enzyme both on the allosteric effect and on the phosphorylating kinase enzyme.

Mevalonat Formation



▪The activity of HMG-CoA reductase is regulated by the cholesterol concentration.

▪As the cholesterol concentration increases, the enzyme is allosterically inhibited and leads to the formation of cholesterol derivates.

▪ In addition, high levels of cholesterol leads to increased degradation and reduced enzyme synthesis.

Mevalonat Formation



▪Mevalonate is converted to isopentenyl pyrophosphate

by a second phosphorylation and decarboxylation as a

result of a series of enzymatic reactions.

• With two phosphorylation and one decarboxylation event, it is

converted into isopentenyl pyrophosphate, a molecule with 5

carbons.

Conversion to Isoprenoid Units



▪An isomerase enzyme combines isopentenyl

pyrophosphate with isomeric dimethylallyl

pyrophosphate to form 10 carbon geranyl

pyrophosphate.

▪The ten carbon geranyl pyrophosphate associates with

isopentenyl pyrophosphate to form the 15 carbon

farnesyl pyrophosphate.

▪Then the two molecules farnesyl combines to form 30

carbons to the squalene.

Squalene Formation



▪This phase between squalene and cholesterol is very detailed and complex.

▪The main ingredient, lanosterol, can accumulate approximately as much as the amount of cholesterol that is actively synthesized in the cell.

▪At the stage between squalene and lanosterol, an oxygen atom is needed to form four steroid nuclei.

Cholesterol Transformation



▪Cyclization occurs in one step with electrons taken from neighboring double bonds.

▪The conversion of lanosterol to cholesterol occurs in a very staged manner, which requires the methyl group, oxidation and decarboxylation.

▪ It is believed that many different enzymes are involved between lanosterol and cholesterol. However, the main way is not clear.

Cholesterol Transformation




Acetyl-CoA



▪ Synthesized cholesterol and most of the intermediates

formed during synthesis and isopentenyl pyrophosphate

with five carbons form• Fat-soluble vitamins,

• Terpenes,

• Ubiquinone and

• The source of many substances such as phytol, the side

chain of chloroplast in plants.

Relationship between cholesterol metabolism and other

compounds in the cell



▪Cholesterol is the main source of bile, which has

significant in digestion.

▪Vitamin D is effective in the absorption of calcium from

the intestines.

▪Testosterone and hormones like ApoA, B, C, 17β-

estradiol are steroid hormones.





▪The source of the steroid hormones that regulate the

electrolyte balance is also cholesterol.

▪Another important feature of cholesterol is the ability to

regulate membrane fluidity through cell membrane

structure.





▪Two thirds of plasma cholesterol is esterified with long chain fatty acids, especially linoleic acid.

▪Cholesterol esters are continuously hydrolyzed and re-synthesized.

▪The hydrolysis takes place in the liver. The re-expression occurs mainly by transferring a fatty acid residue from the lecithin under the influence of lecithin cholesterol transferase (LCAT) in the plasma.

Plasma Cholesterol



▪Cholesterol is transported as free molecules or fatty acid esters in lipoproteins.

▪ Plasma cholesterol and triglycerides have been known for a number of years and therefore the severity of age and stress on vascular diseases has been known for many years.

▪As a result of excess stress, adrenaline secretes excess free fatty acids from fat tissues, which increases the synthesis of low-density lipoproteins (LDL) in the liver.

Plasma Cholesterol



▪ It allows some substances in the plasma to be

transported as it is not saturated.

▪ It is the precursor of some steroid hormones.

▪ 7-dehydrocholesterol is transformed into Vitamin D3 by

ultraviolet light at the skin.

Functions of Cholesterol



Lipoproteins



Lipoproteins

▪ Some lipids combine with specific proteins to form lipoproteins.

▪ Plasma lipoproteins include lipids such as cholesterol and its esters, and triacylglycerols.

▪ Blood plasma lipoproteins are classified according to the particles of lipids and their concentrations which they contain. There are mainly 4 groups (+1 intermediate) and they contain 50-90% lipid.



▪Chylomicrons (CM): They carry the triacylglycerols to

the tissues from intestine.

▪Very Low Density Lipoproteins (VLDL): They contain

triacylglycerols that are synthesized in the liver.

▪ Intermediate Density Lipoproteins (IDL): Intermediate

lipoproteins.

Lipoproteins



▪ Low Density Lipoproteins (LDL): They are formed by the

breakdown of lipid fractions of very low-density lipoproteins.

They allow cholesterol to be transported to tissues outside the

liver. It regulates cholesterol metabolism in tissues outside the

liver. It is the lipoprotein that contains the most cholesterol

concentration.

▪ High Density Lipoproteins (HDL): Proteins and phospholipids are

present in excess in this lipoprotein. It allows cholesterol to be

transported from the various tissues to the liver.

Lipoproteins



Lipoproteins

TG (%87) TG (%57)




▪ Lipoproteins are spherical structures consisting of a

neutral lipid core (triglyceride or cholesterol ester or

both) and a shell consisting of apoproteins, phospholipids

and free cholesterol (polar lipids) around it.

▪ Plasma lipoproteins are synthesized and secreted by the

liver and intestine.

Lipoproteins



▪ Proteins involved in the structure of lipoproteins are called

apolipoproteins or apoproteins.

▪These are classified as Apo-A, Apo-B, Apo-C and Apo-E.

Each has subfractions.

▪These apoproteins are synthesized and their lipoproteins

differ.• The protein components of these structures organize the

entry and exit of particulate lipids into specific locations.

Lipoproteins



Lipoprotein Structure




http://www4.uwsp.edu/chemistry/tzamis/ch260/lipoprotein.jpg

Classification of Lipoproteins

▪ Lipoproteins are classified according to their

specificities in their differences in protein and lipid

ratios.

▪The most widely accepted classification of plasma

lipoproteins is by ultracentrifugation.

▪There are 5 lipoproteins.




▪Chylomicrons• The widest/lowest-density lipoproteins, triacylglycerols,

cholesterol and other lipids in nutrients are transported to the

fatty tissues of the intestines and to the liver.

• It mainly contains 82% triglycerides. In addition, it contains 2%

apoprotein, 7% phospholipid and 9% cholesterol.

• Apo-A series, B-48, Apo-C and Apo E family apoproteins.

• Chylomicrons are synthesized in the small intestine.

• Their function is to carry the dietary lipids (triglycerides,

cholesterol, fatty acids) to the tissues.




• The chylomicrons synthesized in enterocytes first enter the

lymph circulation then systemic circulation.

• Triacylglycerols in the chylomicrons are hydrolyzed by lipases

localized in the capillaries of adipose tissue and other

peripheral tissues within minutes.

• The chylomicron molecule, which undergoes triglyceride loss,

is called the residue chylomicron. This molecule includes

cholesterol, Apo-B and Apo-E molecules.

• Residual chylomicrons are taken from the circulation by the

liver.



▪Very low-density lipoproteins (VLDL)• VLDLs are synthesized in the liver.

• VLDLs consist of 52% triglyceride, 18% phospholipid, 22% cholesterol, 8% apolipoprotein in structure.

• Sphingomyelin and lecithin are the main phospholipids.

• It contains 30-35% Apo-B100 as apolipoprotein. The rest are the C and E series. It contains A serie in trace amounts.

• VLDL leaves endogenously synthesized triacylglycerols in adipose tissue.

• Cholesterol residues are transported with low-density lipoproteins (LDL) rich in cholesterol esters.




▪ Intermediate-density lipoprotein (IDL)• VLDLs become IDL (intermediate-density lipoprotein) (in

other words VLDL residues) when TGs in VLDL start to

hydrolyse with extrahepatic LPL effect.

• IDLs have equal cholesterol and triglycerides in cats and dogs,

and there are two possible ways.1. Cleared by the liver or

2. Converted to LDL.




▪ Low-density lipoproteins (LDL)

• The richest lipoprotein in means of cholesterol content.

LDLs carry the cholesterol to extrahepatic tissues and

allow it to be stored there.

• It is a product of the catabolism of VLDL.

• Its structure contains 47% cholesterol, 9% triglyceride, 21%

apoprotein, 23% phospholipid.

• The main apolipoprotein is Apo-B100. Total plasma

contains 90-95% of Apo-B100.




• VLDL leaves endogenously synthesized triacylglycerols in

adipose tissue. Cholesterol residues are transported with low-

density lipoproteins (LDL) rich in cholesterol esters. Most of

the LDL cholesterol is linoleate esterified, which is a

polyunsaturated fatty acid.

• The role of LDL is to carry cholesterol to peripheral tissues and

regulate cholesterol synthesis in these locations.




▪High-density lipoproteins (HDL) • HDLs are mainly liver-derived lipoproteins.

• The structure contains 45% apoprotein, 26% phospholipid, 8%

triglyceride and 21% cholesterol.

• 80% of the phospholipids in the structure are lecithin. This

phospholipid plays an important role in the esterification of

cholesterol with LCAT.

• HDLs serve as a repository for Apo-A, Apo-E and Apo-C.

• The role of HDL is to carry cholesterol from the peripheral

tissues to the liver.




• There are two subfractions of HDL.

1. HDL3: Take cholesterol from peripheral tissues.

2. HDL2: It is formed by esterifying cholesterol with HDL3 LCAT

effect. HDL2 is also degraded by hepatic triglyceride lipase

in the liver.




Source: ApsuBiology



http://www.apsubiology.org/anatomy/2020/2020_Exam_Reviews/Exam_4/CH24_Lipid_Metabolism.htm

http://www.apsubiology.org/anatomy/2020/2020_Exam_Reviews/Exam_4/CH24_Lipid_Metabolism.htm

▪ Starvation: Lipoprotein changes are induced in fasting

conditions in pigs that are 3 days old or more, and under

these conditions, the plasma VLDL concentration

increases.

▪Diet and Nutrition: In the absence of long chain

essential fatty acids, lipoprotein transport from the

liver, LPL activity, LCAT activity and fatty acid synthesis

are affected.

Factors Affecting Lipoprotein Metabolism



▪Liver Disorders: Significant amounts of LDL cholesterol and phospholipid levels are observed in the fatty liver of animals.

▪Pancreatitis: In acute pancreatitis, LPL inhibits VLDL and chylomicrons, which cause cancellation, and causeshyperlipidemia.

▪Diabetes: Diabetes mellitus, secondary pancreatic disorders caused by insulin insufficiency, causes hyperlipidemia.




▪ Exercise: Exercise in dogs causes changes in lipoprotein

metabolism. Intensive physical exercise causes an

increase in LPL activity.

▪Hypothyroidism: It has been observed in a study

conducted in an atrial setting that hypothyroidism

changes lipoprotein concentrations. Experimental

hypothyroidism induced by thyroidectomy significantly

increased blood VLDL and VLDL subfractions at 4 weeks.




▪ Life style: Lifestyle also affects the lipoprotein profile.

The ratio of fat in the diet, the intensity of the exercise

and the shelter conditions affect the amount of

lipoprotein.

▪Age: Age affects the lipoprotein profile in animals.

▪ Sex: Generally, HDL protein and cholesterol levels are

lower in males than females.




▪Weight loss or gain: When plasma cholesterol and

lipoprotein concentrations are compared with baseline

values, these values increase in weight gain. Loss of

lipoprotein fractions in the absence of HDL is observed.




Ketone Bodies



▪ Further oxidation of Acetyl CoA, which occurs in the

oxidation of fatty acids, follows two pathways in the

liver.

▪These are produced by the citric acid cycle. It is the

way to the ketone bodies which are,• Acetoacetate,

• β-hydroxybutyrate and

• Acetone.

Ketone Bodies



▪Acetoacetate and β-hydroxybutyrate can not be more oxidized in the liver (adult).

▪Transferred to the blood circulation and peripheral tissues, these tissues are oxidized and energized by the citric acid cycle.

▪Keton bodies are an alternative fuel for cells. Due to their water-solubility properties, it is not necessary to carry within lipoproteins or with albumin.

Ketone Bodies



▪Acetyl CoAs present in the liver are produced when

they reach the oxidative capacity in the liver, thus

protecting the energy.

▪ Extrahepatic tissues such as skeletal muscle, heart

and renal cortex use ketone bodies in proportion to the

blood levels.

▪Brain tissue can also use ketone bodies if the levels are

high enough.

Ketone Bodies



1. The first step in the formation of acetoacetate in liver

mitochondria is the enzymatic condensation of two

acetyl-CoA. This reaction is catalyzed by thiolase.

2. Then, Acetoacetyl CoA reacts again with an H2O and

an Acetyl-CoA, and 3-hydroxy-3-methylglutaryl CoA

(HMG-CoA) forms.

Ketone Bodies



3. In the subsequent reaction, acetoacetate and acetyl

CoA occur. The reaction is catalyzed by 3-hydroxy-3-

methylglutaryl CoA Lyase.

4. The resulting acetoacetate is reduced to β-

hydroxybutyrate.• Acetoacetate also acts as a precursor molecule for acetone.

It is spontaneously or enzymatically converted to acetone.

Ketone Bodies



▪Acetoacetate and β-hydroxybutyrate, formed by 2

enzymatic steps from 2 acetyl-CoA in the liver, pass into

blood from liver cells and are transported to peripheral

tissues.

▪ In peripheral tissues, β-hydroxybutyrate is oxidized to

Acetoacetate by β-Hydroxybutyrate dehydrogenase.

▪Acetoacetate is activated by transferring a CoA-SH from

succinyl CoA and forming CoA-SH ester of acetoacetate.

Ketone Bodies



▪The resulting Acetoacetyl-CoA is degraded by the

thiolase enzyme to 2 acetyl-CoA.

▪The resulting acetyl-CoAs enter the citric acid cycle in

the peripheral tissues and become fully oxidized.

▪ It is usually difficult to oxidize a small amount of

acetone in the organism.

▪The liver does not use ketone bodies, although it is the

place where ketone bodies are synthesized in the

organism.

Ketone Bodies



▪The concentration of ketone bodies in the blood of well-

fed mammals normally does not exceed 0.2 mmol/L.

▪ In ruminants this ratio is somewhat higher due to the

formation of β-hydroxybutyrate from butyric acid on

the rumen wall.

▪ Increase in blood concentration of ketone bodies are

called ketonemia, excration via urine is called

ketonuria, the whole is called ketosis.

Ketone Bodies



▪Acetoacetate and β-hydroxybutyrate are both

moderately strong acids.

▪They are buffered when they are in blood or tissues.

▪These outcrops, which are continuously excreted in

large quantities, drain the alkali reservoir, causing the

loss of buffering cations that lead to ketoacidosis. This

can be particularly dangerous to diabetes mellitus.

Ketone Bodies



▪The pathological features of ketosis occur due to

diabetic mellitus, pregnancy toxemia and dairy

cattle ketosis; non-pathological forms are

observed in fasting, high fat feeding and long-

term exercises.

Ketone Bodies



Origin and Utilization of Ketone Bodies




Source: Engelgink, 2014Source: Engelgink, 2014



Fatty Liver and

Lipotropic Factor



▪ In liver cells, the appearance of diffuse fat infiltration

and degeneration is expressed as fatty liver syndrome

(Fatty Liver Syndrome). Liver fat is called

LIPOTROPISM.

▪Methionine, Choline, Betaine and Inositol are

substances that prevent fatty substances in the liver.

These items are called LIPOTROPIC MATTERS.

Fatty Liver and Lipotropic Factor



▪Fatty Liver Syndrome• The lipid ratio in the liver reaches 25-30%.

• The diameter of the fat droplets is 2-10 microns.

• It is characterized by the formation of fat cysts

up to 100 microns in size.




▪Nutritional factors• Excess fat diet

• Excess carbohydrate nutrition

• Protein-poor nutrition

• Hunger

• Lipotropic substance deficiency

• Insufficiency of essential fatty acids

• Tiamin and biotin excess

• Chronic alcoholism




▪ Endocrine Disorders• Pituitary-related disorders

• Cortical disorders

• Thyroid disorders

• Insulin disorders

• Sex hormone disorders

▪Other disorders• Central nervous system disorders

• Obesity




▪Toxic Factors• Chemical factorso Carbon tetrachloride

o Chloroform

o Phosphorus

• Bacterial factors

• Anoxid factorso Anemia

o The congestion




Hormonal Control of

Lipid Metabolism



▪ Insulin reduces the concentration of unesterified fatty

acids (NEFA) in the blood plasma by reducing the rate of

separation of fat from adipose tissues.

▪ Stimulates Pentose-phosphate shunt for the use of

glucose 6-phosphate via this pathway. Thus, the

synthesis of NADPH and fatty acids increases.

Hormonal Control of Lipid Metabolism



▪Adrenaline stimulates the mobilization of fat from fat deposits, and thus increases the concentration of NEFA in the plasma.

▪ACTH, TSH and glucagon hormones also stimulate fat mobilization from adipose tissue. • These hormones stimulate C-AMP as a secondary messenger,

whereas Prostaglandin E1 shows the opposite of these effects.

• Growth hormone also stimulates fat mobilization.

• Glucocorticoid applications affect fat metabolism through carbohydrate metabolism.

Hormonal Control of Lipid Metabolism



Question 1

Answer: E

▪Which of the following reactions does not occur during the breakdown of fatty acids?

a. Thiolysis

b. Hydration

c. Dehydrogenation I

d. Dehydrogenation II

e. Denaturation



Question 2

Answer: D

▪Which of the following tissues can not use ketone bodies for energy purposes?

a. Kidney

b. Brain

c. Skeletal Muscle

d. Adult Liver

e. Intestine



Your Questions?Send to [email protected]



mailto:[email protected]

▪ Ası. T. 1999. Tablolarla Biyokimya, Cilt 2

▪ Engelking LR. 2014. Textbook of Veterinary Physiological Chemistry. 3rd

edn. Academic Press.

▪ Eren Meryem. Prof.Dr. Ders Notları (Teşekkürlerimle)

▪ Fidancı Ulvi Reha. Prof. Dr. Ders Notları (Teşekkürlerimle) • http://80.251.40.59/veterinary.ankara.edu.tr/fidanci/Ders_Notlari/LM-Keton_Cisimleri.pdf

▪ Sözbilir Bayşu N, Bayşu N. 2008. Biyokimya. Güneş Tıp Kitapevleri, Ankara

References



http://80.251.40.59/veterinary.ankara.edu.tr/fidanci/Ders_Notlari/LM-Keton_Cisimleri.pdf

Next Chapter;

PROTEIN METABOLISM



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