Introduction to Lipid Metabolism

Objectives
Fatty acid beta-oxidation to make acetyl-CoA and ATP Ketone bodies formation (Ketogenesis) Ketoacidosis Gluconeogenesis by fatty acid beta-oxidation

Lipid Digestion by Lipases

In mouth: Lipase In stomach: Gastric lipase In pancreas: Lipase + Co-lipase In duodinum: Emulsification In intestine: Cholesterol esterase, Phospholipase A2

Lipases break down Triacylglycerols into Fatty acids and Glycerol Lipid absorption is in form of micelles

Fatty Acid
Palmitic Acid 16:0
3 -CoA.SH

Fatty Acid+CoA.SH Fatty Acyl-CoA Active fatty acid means Fatty Acyl-Coenzyme A

Fatty Acid Oxidation makes Acetyl-CoA

Fatty acid oxidation in mitochondria and fatty acid biosynthesis in the cytosol By fatty acid oxidation, fatty acyl-CoA derivatives, specific enzymes, Oxygen, NAD+ and FAD coenzymes generate acetyl-CoA ATP Beta oxidation: beta carbon on fatty acid is converted to beta-keto acid.

Two enzymes catalyze Acyl-CoA formation

Activation of Fatty Acids in cytoplasm Fatty acyl CoA Synthase(Thiokinase) Carnitine Acyl Transferase

8 Fatty acid acyl CoA converted to 8 Acetyl CoA (8 acetyl CoA make 80 ATP) Each acetyl CoA molecules generate 10 ATP

Carnitine
-hydroxy- -trimethylammonium butyrate) (CH3)3N+CH2CH(OH)CH2COO

Carnitine is a transporter Carnitine activates fatty acid(Fatty Acyl-CoA) Carnitine-Acyl Transferase-I` Carnitine-Acyl Transferase II (TRANSLOCASE) Medical Biochemistry explains -CARNITINE DEFICIENCY and -TRANSLOCASE DEFICIENCY

Beta Oxidation in 5 Steps

Acyl CoA Synthase FAD linked Dehydrogenase Hydration NAD dependent Dehydrogenase Cleavage Net Outcome of Palmitic acid oxidation: FAD, NAD ATP Yield (Energetics) 106 Regulation: glucagon; insulin ratio, CAT-I
(Palmitic acid )C18

Carnitine in -Oxidation
CARNITINE ACYLTRANSFERASE CPT-I

-2 ATP

+1.5ATP

7 cycles
+2.5ATP

C16C14 C148 acetyl-CoA (7 cycles)

10 x 8 ATP

Net 78 ATP +28 ATP

Fatty Acid Oxidation Reactions

Fatty Acid 16Carbons -2 C

-2 C

-2C

Unsaturated Fatty Acid Oxidation

Fatty Acid Oxidation with an Odd Number of Carbon Atoms Yields Acetyl-CoA + PropionylCoA

Ketone Bodies
Acetyl CoA makes Ketone Bodies if Carbohydrates are high in liver LIPIDS BURN IN FLAME OF CARBOHYDRATES Ketone Bodies are: Acetoacetate, Hydroxybutyric Acids and Acetone

Ketogenesis in Starvation (High carb available)

LIVER Fatty AcidAcyl CoA Glucose2Acetyl CoA
Acetoacetyl CoA Synthase HydroxyMethyl CoA Lyase Acetyl CoA

LUNGS

FFA Liver Ketone bodies Blood

2CO2 TCA

Lungs
Kidney
Mitochondrial NAD/NADH Ratio URINE

Muscle

Ketone Bodies Serve as a Fuel (Ketolysis) in Extrahepatic Tissues

Thiophorase

Lung
BLOOD

Kidney

Regulation of Ketogenesis
High Glucagon: Insulin Ratio in Blood Lipolysis (Lipase) CAT-I (Carnitine Acyl Transferase-I) Acetyl CoA conversion to Ketone bodies High Gluconeogenesis Medical biochemistry explains Ketosis: Metabolic Acidosis; Reduced buffers; Acetone smell; Osmotic diuresis and dehydration; Sodium loss; Coma due to Dehydration-Acidosis-Hypokalemia

Disorders of Ketogenesis
CPT-I deficiency: Impaired Fatty Acid Oxidation Gives Rise to Hypoglycemia, muscle weakness Jamaican Vomiting Sickness: Deficiency of acylCoA Dehydrogenase and Dicarboxylic Aciduria Refsum disease: Phytanic Acid deposits Zellwegers Cerebro-hepato-renal disease: Polyenoic acid deposits Ketosis develops Ketoacidosis

Fatty acid Synthesis

Acetyl CoA + CO2 Malonyl CoA
CE-SH Transacetylase ATP ADP + Pi Transacetylase ACP-SH Acetyl CoA Carboxylase

Acetyl-S-CE
CO2 NADP

+ Acetoacetyl ACP NADPH

Reductase
H2O

Malonyl-S ACP
Synthase

Betahydroxy Butaryl ACP

Enoyl ACP

Dehydratase
Reductase

(x 6 cycles)

NADPH NADP

Butyryl ACP(4C)
Thioesterase

+ H2O

Palmitic Acid (16C)

Fatty Acid Acyl Synthase Complex contains: Ketacyl synthase, A- and MTransacetylase, Hydratase, Reductase, ACP, Thioesterase

Fatty Acyl Synthase Complex

Diseases of Fatty Acid Biosynthesis

Linolenic acid Arachidonic Acid Omega 3, Omega 6 PUFA Cystic fibrosis, Crohn disease,Cirrhosis, Reyes syndrome, Zellwegers Syndrome due to low essential fatty acids

Arachidonic Acid Makes Prostaglandins and Leukotrienes

Arachidonic Acid Cyclooxygenase Lipooxygenase Prostaglandins 5HPETE
(with 2 double bonds)

Prostaglandins Thromboxanes

LTA4 LTB4 LTC4 LTD4 LTE4

Cholesterol and Lipoproteins

Cholesterol is steroid Plasma Lipids are LIPOPROTEINS Lipid Profile: Triglycerides;Lipoproteins;Cholesterol

Cholesterol
Cholesterol makes Prostenoids, Sterols, Bile Acids, Vitamin D Complex molecules consisting of four fused carbon rings

Cyclo-pentano-perhydrophenanthrene ring (CPP)

Cholesterol: 3-hydroxy-5,6-cholestene

Condensation of 2 Acetyl-CoA

Cholesterol Biosynthesis

Synthase
HMG CoA formation

HMG CoA Reductase

Mevalonate Formation

Kinase, Decarboxylase
Isopentanyl Pyrophosphate

Transferase
Geranyl Pyrophosphate

Transferase
Farnesyl Pyrophosphate

Squalene Synthetase
Squalene

Epoxidase
Lanosterol

Cyclase
Zymosterol
Desmosterol Cholesterol

Cholesterol Breakdown
Cholesterol makes mevalonate Cholesterol 7 Hydroxylase Cholesterol HydroxyCholesterol HMG CoA Reductase Mevalonate HMG CoA
Cholesterol Cholestane 3,7,12Triol Cholestane 3,7 diol Cholic Acid Chenodeoxycholic Acid Cholyl CoA ChenodeoxycholylCoA Glycine Taurine Glycocholic Tauro CDCA Acid Cholesterol 7-DehydrocholesterolProD3 25 OH-Cholecalciferol Vitamin D3 1,24,25 Tri OH-D3

Cholesterol Pregnanolone Progesterone 17 Hydroxyprogesterone Corticosterone

Cortisol

Androstenedione Aldosterone Testosterone 17 Estradiol Estriol

Separation of Lipoproteins
Centrifuge separates Lipoproteins at different densities: Chylomicrons (Apo B-48) in intestine Very Low density (Apo B-100) in liver Intermediate density Low density (Apo B-100) High density (Apo-A)

Lipid Transport and Metabolism

LDL Lipoproteins: Receptors HDL: HDL1, HDL2, HDL3 in TAG and Cholesterol metabolism Liver plays central role(digestion and absorption of lipids,bile,fatty acids,ketogenesis,lipoproteins) Cholesterol + FA Cholesterol Esters HMG-CoA Reductase, PPTase-I, Cholesterol hydroxylase, ACAT, LCAT, AMP Kinase CETP, SRE-BP(Steroid Regulatory Element BP) Apo B-48, Apo B100, Apo CII, Apo E2, Apo D

Chylomicron
TAGFA; Apo-C+Apo-E help in exchange CEC+FA

Type I-Hyperlipoproteinemia)

Endocytosis; Lysosomal breakdown

Type II Hyperlipoproteinemia

VLDL
TAG rich; Transport TAG from liver to tissues; Apo CII TAG exchange from HDL to VLDL B-100 favors endocytosis

CETP

Endocytosis

HDL

Cholesterol

Big size Oversize

Medium size

Oversize

small size

-Apo-A1,Apo-B100,Apo-CII,Apo-E2,Apo-D -TAGCE exchange in VLDL, HDL by CETP -ACAT, LCAT, Enzymes -CETP, SREBP

Medical Biochemistry Explains Diseases of Lipid Transport and Turnover

Fatty Acid:
Carnitine Deficiency Methylmalonic aciduria Ketoacidosis with Diabetes

Phospholipids, Sphingolipids
Respiratory Distress Syndrome Niemann Pick Disease Sphingolipidoses, Gangliosidoses

Cholesterol, Lipoproteins
Hypercholesterolemia Hyperlipoproteinemia Cholelithiasis Atherosclerosis and Dyslipidemia Adrenal Hyperplasia Non-alcoholic Fatty Acid Disease Adipose Tissue and Obesity

Lipoprotein Transport Diseases

Summary
Cholesterol (synthesis and degradation)
HMG CoA Red. and SREBP-2 AMP Kinase and PPTase1

Cholesterol Sterols, Bile Salts, Vit D, Prostaglandins, Sex hormone

Cholesterol 7 Hydroxylase and cholelithiasis

Plasma Lipoproteins (CM,VLDL,LDL,HDL,C)

Receptors, TAG,CE,PL,Apo-P (B-48,B-100,CII,E) Lipoprotein Lipase and Hyper-/Hypolipoproteinemia TAGCE exchange in VLDL, HDL by CETP LDL receptors (HyperLipoProteinemia) and ACAT Apo-A1 induced LCAT

Phospholipids, Phospholipase and Diacylglycerol-Inositol triphosphate PIP2-DAG-PKC cascade Sphingomylin = ceramide(sphingosine +FA)+Phosphocholine (Niemann Pick Dis)
Gangliosidoses, Cerebrosidoses