Lipid metabolism

Catabolism of FA

Oxidation

Anabolism of FA De-novo

synthesis

Ketone body metabolism

Cholesterol metabolism

Lipoprotein

metabolism

Triacylglycerol

Fatty acids

Acetyl CoA

TCA

CO2

Overview of lipid

metabolism

» Fatty acids are stored as Triacylglycerols

» Constitute 84% of stored energy

+ Protein - 15%

+ Carbohydrate (glucose or glycogen) - <1%

» Fatty acids mobilized from Triacylglycerols are

oxidized to meet the energy needs of a cell

Mobilization of FA from TG into tissues

Activation and transportation of FA

into mitochondria Degradation of FA by oxidation into

acetyl-CoA

Lipid Metabolism

Mobilization of FA from TG into tissues

8

Glycolysis

Gluconeogenesis

Lipogenesis

Fats not only obtained from the diet but also obtained from lipogenesis in the body. Lipogenesis means synthesis of fats from CHO and proteins present in excess of body need.

Lipogenesis requires:

1- Synthesis of fatty acids (FA) and glycerol

2- Activation of fatty acids by CoA and glycerol by glycerokinase, 3- Combination of activated fatty acid and glycerol to give TAG (fats).

Site: Cytoplasm of liver, mammary glands and adipose tissues.

Steps:

1- Transport of acetyl CoA to cytoplasm: Acetyl CoA is the precursor of fatty acid synthesis. It is produced from oxidation of glucose (by oxidative decarboxylation of pyruvate) and metabolism of ketogenic and mixed amino acids.

Acetyl CoA is produced in mitochondria, and FA synthesis occurs in cytoplasm, so acetyl CoA must be transferred to cytoplasm across mitochondrial membrane which is impermeable to CoA.

The transport occur through condensation of acetyl CoA inside mitochondria with oxaloacetate (OAA) to form citrate which can be transferred into cytoplasm. In cytoplasm, citrate is cleaved by ATP-citrate lyase or called citrate cleavage system in the presence of ATP and CoA to give acetyl CoA and OAA.

2-Conversion of acetyl CoA into malonyl CoA by acetyl CoA carboxylase

This step is the rate limiting step in FA synthesis and acetyl CoA carboxylase is the rate limiting enzyme.

3- Remaining series of the pathway is catalyzed by fatty acid

synthase which is a multifunctional enzyme.

Reaction catalyzed by Acetyl CoA Carboxylase

Regulation of acetyl CoA carboxylase:

A)Allosteric regulation: allosterically activated by citrate & ATP and inhibited by the end product of the pathway (palmitic acid).

B)B) Hormonal regulation: activated by insulin, inhibited by adrenaline and glucagon (anti-insulin hormone).

C) Dietary regulation: prolonged consumption of high claoric diet (e.g CHO diet) increases the synthesis of acetyl CoA carboxylase and so increase FA synthesis. Fat- free diet, fasting and low CHO reduce enzyme synthesis and so FA synthesis.

Elongation of fatty acids: Mitochondrial synthesis

Palmitic acid - the end product of FA synthesis in cytoplasm

can be elongated in mitochondria by the addition of two carbon

atoms to give other long chain saturated FA e.g. stearic acid

Unsaturation: occur also in mitochondria by desaturase enzyme

to give unsaturated fatty acids e.g. oleic acid

Biosynthesis of TAG from synthesized fatty acid and glycerol:

Site: cytoplasm of liver and adipose tissues

Steps:

1- Activation of fatty acids into acyl CoA

2- Activation of glycerol into 3-glycerophosphate

3-Combination of activated fatty acid and glycerol to form DAG

then TAG as in figure.

A)

CH₂-OH CH-OH CH₂-OH Glycerol

glyc erokinase ATP

ADP

CH₂-OH CH-OH

CH₂-O-PO₃ 3-glycerophosphate

B)

2 RCOOH Fatty acid

2 CoASH thiokinase

2 RC-SCoA O

- 2CoA

CH₂-O-CO-R₁

CH-O-CO-R₂

CH₂-O-PO₃

Phosphatidic acid

Phosphatase

p_i

CH₂O-CO-R₁

CH₂-O-H

CH₂O-CH₃O-R₂

1,2 diacylglycerol (DAG) CDP -choline

Lecithicin

Acyl CoA, acyl transferase

TAG

Synthesis of TAG (for illustration)

- β -oxidation

- Peroxisomal FA oxidation - α -oxidation

- ω -oxidation

- Modified β -oxidation pathway

β Oxidation of fatty acid is oxidation of fatty acid at the β

carbon atom with successive removal of two carbon atoms as

acetyl CoA

1 • Activation of fatty acids in the cytosol

2

• Transport of activated fatty acids in to mitochondria

3 • β -Oxidation proper in the mitochondria

Occurs in outer mitochondrial membrane for long chain fatty acids

Fatty Acid Acyl-CoA

CAT-I

CAT-II

Overall process of β -oxidation

7 Cycles of β –oxidation with Successive removal of

2 carbon units

Palmitoyl-CoA

Oxidation by FAD Hydration

Oxidation by NAD

Thiolysis

oxidation

oxidation hydration

thiolysis

C₁₆

7 rounds

Acetyl-CoA

ENERGETICS OF COMPLETE OXIDATION OF PALMITIC ACID

Oxidation 7 cycles

7 FADH₂ x 2ATP/FADH₂ 14 (10.5)

7 NADH + H⁺ x 3ATP/NADH 21 (17.5)

From 8 acetyl CoA

Each acetyl CoA provides 12 ATP by TCA cycle 96 (80) Total ATP produced from one palmitic acid 131 (108)

Total ATP used for activation 2

NET YIELD OF ATP 129 (106)

Beta Oxidation

Provision of energy

• 20-30% of energy requirement of the cell

• Major pathway

Ketone bodies

• Diabetes

• Starvation

Synthesis of biomolecules from

acetyl CoA

• Acetylcholine

• Cholesterol

Oxidized by β –oxidation in the

same way as that of even number, except the

are the end products

β-OXIDATION OF ODD CHAIN

FATTY ACIDS

D

L

• Requires additional enzymes

• Isomerase and reductase

Presence of double bonds

• Minor pathway

• Involves oxdn of fatty acids at α carbon atom

• One carbon is removed from the carboxyl end and released as CO

₂

• Occurs in endoplasmic reticulum

• Phytanic acid oxidation

α -OXIDATION

 It is a minor pathway

 Takes place in microsomes

 Involves oxidation of last carbon atom ( ω carbon)

 More common with

medium chain fatty acids

Lipid Metabolism

Ketone Bodies

Ketone Bodies

Blood Glucose and

Glucosuria

Ketone Bodies

Cholesterol Metabolism

Cholesterol Structure

FA for esterification It composed of 27 C-atoms

Biological importance of cholesterol

1. Cholesterol is a crucial component of cell membranes

- Cholesterol is compact, rigid, hydrophobic molecule with a polar OH group.

Biological importance of cholesterol

2. Cholesterol is the precursor of bile salts

» They prevent cholesterol from

precipitating in gallbladder in form of gallstones.

» Cholesterol protects gallbladder

membranes from irritating and harmful effects of bile acids.

Biological importance of cholesterol

3. Cholesterol is the precursor of steroid hormones

Cholesterol is the precursor of all steroid hormones including estrogen, progesterone,, testosterone, corticosteroids and aldosterone

4. Cholesterol is a precursor of vitamin D

Dietary Cholesterol

» Found mainly in animal products especially egg yolks, meat, poultry, shellfish and milk.

» About 50% of dietary cholesterol is absorbed

» Increase intake = decreased absorption

Site of cholesterol synthesis

» Cholesterol Synthesis

» Cholesterol is synthesized in the cytosol and endoplasmic reticulum (ER).

» Liver is the main site of cholesterol synthesis; also, it is synthesized in intestine and skin

» Cholesterol is synthesized from acetyl groups of cytosolic acetyl coenzyme A (acetyl-CoA).

» Glucose and fatty acids are the major sources of acetyl-CoA

Cholesterol Synthesis

1) First, 2 acetyl-CoAs are condensed by thiolase enzyme to give acetoacetyl-CoA which condenses with another acetyl-CoA forming hydroxymethylglutaryl CoA (HMG- CoA). The reaction is catalyzed by HMG-CoA synthase.

2) HMG-CoA is reduced to mevalonic acid (C6), this reaction requires 2NADPH. It is catalyzed by HMG-CoA reductase which is regulatory enzyme. This step is the rate limiting step in sterol biosynthesis.

Cholesterol Synthesis

3) Mevalonic acid is phophorylated (utilizes 3 ATPs), dehydrated and decarboxylated to form an activated 5-carbon isoprenoid unit (isopentenyl pyrophosphate, IPP).

4) IPP is isomerized to another activated

isoprene (Dimethylallyl pyrophosphate, DPP).

Cholesterol Synthesis

5) Six units of isoprenoids are condensed to finally produce squalene (30C). Squalene synthase catalyzes the formation of squalene. This is the second reaction in the cholesterol synthesis pathway that requires NADPH as a coenzyme.

Cholesterol Synthesis

6) Squalene is oxidized by squalene monooxygenase using another molecule of NADPH as a coenzyme. Cyclization reaction forms lanosterol

7) Lanosterol is converted into cholesterol in the last series of reactions.

Cholesterol Biosynthetic Pathway

Transport of cholesterol

» In plasma, 30% of cholesterol is free and 70% is in ester form. Due to the insolubility of cholesterol, their redistribution in the body requires specialized carriers capable of solubilizing and unloading them at specific target sites.

» Free cholesterol and most lipids are transported in the blood as part of soluble complexes called lipoproteins.

» Five main classes of lipoproteins based on their size and density called, in order of increasing density, Chylomicrons, Very-low-density lipoprotein (VLDL), Intermediate-density lipoprotein (IDL), Low-density lipoprotein (LDL) and High-density lipoprotein (HDL).

1) Chylomicron which is basically fat droplet containing little protein, pick up dietary cholesterol from the intestine.

2) VLDL, formed in liver and contain excess triacylglycerol and cholesterol, transport cholesterol from liver to plasma. During transport in the bloodstream, VLDL delivers triacylglycerol to tissues leaving IDL molecules, which contain an even higher percentage of cholesterol.

3) The IDL molecules lose triacylglycerols in the bloodstream until they form LDL molecules, which have the highest percentage of cholesterol within them, thus LDL is called “Bad cholesterol”.

Transport of cholesterol

Transport of cholesterol

4) LDL is taken up by peripheral tissues through LDL receptors which recognize Apo-B100. Cholesterol is liberated and stored as cholesterol ester

5) HDL removes cholesterol from extrahepatic tissues and esterifying, thus HDL is called “Good cholesterol”.

6) HDL is taken up by liver after binding with HDL receptors and hydrolyzed to liberate cholesterol. Released cholesterol either enters in the structure of other lipoproteins, bile salts or excreted in bile.

Bile acids & bile salts

» The end products of cholesterol utilization are the bile acids, synthesized in the liver by oxidation.

» Synthesis of bile acids is one of the predominant mechanisms for the excretion of excess cholesterol.

» The most abundant bile acids in human bile are chenodeoxycholic acid and cholic acid that are identified as primary bile acids.

Hypercholesterolemia

» Elevated level of blood cholesterol; higher concentrations of LDL and lower concentrations of functional HDL are strongly associated with cardiovascular disease because these promote athersclerosis which leads to myocardial infarction and stroke.

» The normal range for total blood cholesterol is 140 to 200 mg/dl.

Lipogenesis

COMPLEX LIPID METABOLISM

Phospholipids are: ˃ Phospholipids metabolism

˃ major constituents of all cell membranes

˃ components of bile

˃ signal mediators

Properties of phospholipids

» Phospholipids are amphipathic molecules

» Head group = alcohol attached via phosphodiester linkage to either:

˃ diacylglycerol (glycerophospholipid) or

˃ sphingosine (sphingophospholipid = sphingomyelin).

Types of

phospholipids

» The simplest glycerophospholipid is phosphatidic acid (PA)

» It consists of glycerol, phosphate, and 2 fatty acyl chains

in ester linkages

Phospholipid degradation

» Glycerophospholipid degradation occurs by phospholipases present in tissues (membrane bound or free), pancreatic juice, and venoms

» Phospholipases are specific for ester bonds in the glycero-phospholipids:

phospholipases A₁, A₂, C, and D

» Glycolipids

» Glycolipids are derivatives of ceramides and sphingosine with carbohydrate directly attached to ceramide

» In contrast to sphingomyelin they do not have a phosphocholine group

» Glycolipids are essential components of cell plasma membranes , but are most abundant in nervous tissues

Outside

Inside

Roles of glycolipids

» Glycolipids have important roles in cell interactions, growth, and development

» They are very antigenic (e.g., blood group

antigens);

Glycolipid structure

— cerebrosides

» The carbohydrate component is linked by an O-glycosidic bond to ceramide

» Cerebrosides contain a single sugar (Galactose); they are abundant in brain and myelin

Know Your Lipid Profile

Total Cholesterol < 200 mg/dl

LDL-Cholesterol < 100 mg/dl

HDL-Cholesterol ≥ 60 mg/dl

Triglycerides < 150 mg/dl

Fasting Blood Level Ideal, Healthy Level

Know Your Lipid Profile