LIPID METABOLISM

LIPOGENESIS

FATTY ACID SYNTHESIS DE NOVO FFA in the blood come from :- (a) Dietary fat (b) Dietary carbohydrate/protein in excess of need FA TAG Site of synthesis:- (a) Liver (b) Lactating mammary gland (c) Adipose tissue

FATTY ACID SYNTHESIS DE NOVO Site of synthesis in cell:- Cytosol Requirements:- Acetyl CoA to supply C to increase chain length ATP NADPH

1.PRODUCTION OF MITOCHONDRIAL ACETYL CoA Acetyl CoA is produced in mitochondria by:- Pyruvate oxidation Acetyl CoA Fatty acid catabolism Acetyl CoA Ketone bodies catabolism Acetyl CoA Ketogenic amino acids catabolism Acetyl CoA

2. PRODUCTION OF CYTOSOLIC ACETYL CoA CoA cannot cross Inner mitochondrial membrane Acetyl portion enters cytosol as CITRATE by condensing with Oxaloacetate ATP TCA Citrate in mitochondria(accumulates) Citrate in cytosol High energy signal Cytosolic acyl CoA ATP(needed for FA synthesis) + Citrate Cytosolic Citrate ATP Citrate Lyase Cytosolic acetyl CoA + OAA

PRODUCTION OF CYTOSOLIC ACETYL CoA

3. FORMATION OF MALONYL CoA Acetyl CoA + CO2 Malonyl CoA Enzyme is Acetyl CoA Carboxylase Requires :- CO2, ATP, Coenzyme Biotin bound to lysyl residue on Carboxylase Rate limiting and regulated step Inactive ACC is a protomer allosteric activation by Citrate polymerization of protomers active ACC LCFA CoA(end product) allosteric inactivation Epinephrine/ Glucagon AMP activated protein kinase(ampk) phosphorylates inactivates ACC Insulin dephosphorylates ACC activates

FORMATION OF MALONYL CoA

REGULATION OF ACETYL CoA CARBOXYLASE

LONG TERM REGULATION OF ACC Prolonged dietary excess :- Calories/ Carbohydrate Insulin ACC synthesis+ Fatty acid synthase FA synthesis Prolonged Calorie / Fat diet ACC synthesis FA synthesis Metformin (anti Diabetic drug) Blood glucose and AMPK ACC TAG

4. ACTION OF FATTY ACID SYNTHASE Fatty acid synthase is a dimer with 7 enzyme activities and a domain which binds 4 -phosphopantetheine 1. Acetyl CoA-ACP Acetyl transacylase:- Acetyl CoA acetate to SH group of ACP

ACTION OF FATTY ACID SYNTHASE 2. Two C fragment shifts to Thiol group of Cysteine:-

ACTION OF FATTY ACID SYNTHASE 3. Malonyl CoA ACP transacylase:- Malonyl CoA Malonate vacant ACP:-

ACTION OF FATTY ACID SYNTHASE 4. 3-Ketoacyl-ACP synthase:- Acetyl group on Cysteine residue condenses with Malonyl group on ACP CO2 released 4C unit attached to ACP Energy released

ACTION OF FATTY ACID SYNTHASE 5. 3-Ketoacyl ACP reductase:- Keto group is reduced to an alcohol

ACTION OF FATTY ACID SYNTHASE 6. 3-Hydroxyacyl-ACP dehydratase:- A molecule of water removed double bond between C2 and C3

ACTION OF FATTY ACID SYNTHASE 7. Enoyl ACP reductase reduces the double bond

ACTION OF FATTY ACID SYNTHASE 4 C Butyryl molecule with 3 saturated terminal C, attached to ACP Butyryl transferred from ACP to Cysteine residue Malonate attaches to ACP 7 steps repeated Hexanoyl-ACP generated Cycle repeated incorporating 2C units every time(from malonyl CoA) at Carboxyl end When FA chain = 16 C synthetic process terminates Palmitoyl S-ACP Palmitoyl thioesterase cleaves the thio ester bond Palmitate(16:0) All the C in Palmitic acid are derived from Malonyl CoA, except acetyl COA, which are at Methyl end of FA.

SOURCES OF NADPH FOR FATTY ACID SYNTHESIS 1. HMP SHUNT:- 2 NADPH/ glucose 2. Cytosolic conversion of Citrate OAA Malate Pyruvate Cytosolic NADPH 3. Glycolysis cytosolic NADH converts OAA to Malate (Carbohydrate metabolism linked to Lipid metabolism)

CYTOSOLIC GENERATION OF NADPH

ELONGATION OF FATTY ACID CHAIN Palmitate (16:0) is end product (LCFA) It can be elongated by +2C units each time in SER Malonyl CoA is the 2C donor NADPH gives the electrons Brain can synthesize >22C FA (VLCFA)

DESATURATION OF FATTY ACID CHAINS DESATURASES present in SER add cis double bonds Require O2, NADH, cytochrome b5, FAD linked Reductase 1 st double bond is between C9 and 10 Oleic acid=18:1(9) + small amounts of Palmito oleic acid=16:1(9) Humans have C 9,6, 5, 4 Desaturases but cannot introduce double bonds between C10 ω end of chain Thus Linoleic(ω6) and Linolenic acids(ω3) are essential FA

STORAGE OF FA AS TAG FA are esterified with glycerol through Carboxyl groups Neutral fat C1 FA is saturated, C2 FA unsaturated, C3 FA can be either TAG is not soluble in water coalesce to form anhydrous, oily droplets in cytosol of adipocytes Major energy reserve of body

SYNTHESIS OF TAG 1. Synthesis of Glycerol 3 P :- Liver is primary site for TAG synthesis Liver/Adipose tissue:- Glucose(glycolysis) DHAP reduced by Glycerol P dehydrogenase Glycerol 3 P Liver:- Glycerol Kinase converts Glycerol Glycerol P When plasma glucose/insulin levels are low Glucose cannot enter adipocyte (GLUT4 is Insulin dependent) adipocytes ᴓ glycerol P synthesis TAG synthesis

PRODUCTION OF GLYCEROL PHOSPHATE

SYNTHESIS OF TAG 2. Activation of Fatty acid:- {Fatty acyl CoA synthetase / Thiokinase} FFA attached to CoA activated

SYNTHESIS OF TAG Sequential addition of 2 FA from fatty acyl CoA (Acyl transferase) Lyso phophatidic acid + CoA Phosphatidic acid (DAG. P.) + CoA Removal of P (Phosphatase) DAG + Pi Addition of the third FA (Acyl transferase) TAG + CoA

SYNTHESIS OF TAG

FATE OF TAG IN LIVER/WAT Starvation:- (a) White adipose tissue anhydrous TAG droplets/ Depot fat mobilized when required for energy Liver does not store TAG, rather VLDL lipid delivered to peripheral tissue