Introduction to Lipid Metabolism

7/22/2019 Introduction to Lipid Metabolism

1/33

Introduction to Lipid Metabolism


2/33

Objectives

Fatty acid beta-oxidation to make acetyl-CoA

and ATP

Ketone bodies formation (Ketogenesis)

Ketoacidosis

Gluconeogenesis by fatty acid beta-oxidation


3/33

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 acidsand Glycerol

Lipid absorption is in form of micelles


4/33

Fatty Acid

Palmitic Acid 16:0

Fatty Acid+CoA.SHFatty Acyl-CoA

Active fatty acid means Fatty Acyl-Coenzyme A

3

-CoA.SH


5/33

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-CoAATP

Beta oxidation: beta carbon on fatty acid is

converted to beta-keto acid.


6/33

Two enzymes catalyze Acyl-CoA formation

Activation of Fatty Acids in cytoplasmFatty 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


7/33

Carnitine

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

-hydroxy- -trimethylammonium butyrate)

(CH3)3N+CH2CH(OH)CH2COO


8/33

Beta Oxidation in 5 Steps(Palmitic acid )C18

Acyl CoA SynthaseFAD linked Dehydrogenase

Hydration

NAD dependent DehydrogenaseCleavage

Net Outcome of Palmitic acid oxidation: FAD, NAD

ATP Yield (Energetics) 106

Regulation: glucagon; insulin ratio, CAT-I


9/33

Carnitine in -Oxidation

C16C14

C148 acetyl-CoA

(7 cycles)

Net 78 ATP

10 x 8 ATP +28 ATP

CARNITINE

ACYLTRANSFERASECPT-I

7 cycles

-2 ATP

+1.5ATP

+2.5ATP


10/33

Fatty Acid Oxidation ReactionsFatty Acid

16Carbons

-2 C

-2 C

-2C


11/33

Unsaturated Fatty Acid Oxidation

Fatty Acid Oxidation with an Odd Number of

Carbon Atoms Yields Acetyl-CoA + Propionyl-

CoA


12/33

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


13/33

Ketogenesis in Starvation (High carb available)

Mitochondrial

NAD/NADH Ratio

Fatty Acid

Acyl CoA

Glucose2Acetyl CoA

2CO2 TCA

LIVER LUNGS

URINE

FFA

LiverKetone bodies

Blood

Lungs

Kidney

Muscle

Acetoacetyl CoA

Synthase

HydroxyMethyl CoA

Lyase Acetyl CoA

d l ( l )


14/33

Ketone Bodies Serve as a Fuel (Ketolysis) in

Extrahepatic Tissues

BLOOD

2

Thiophorase

Lung

Kidney


15/33

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: MetabolicAcidosis; Reduced buffers; Acetone smell; Osmoticdiuresis and dehydration; Sodium loss; Coma dueto Dehydration-Acidosis-Hypokalemia


16/33

Disorders of Ketogenesis

CPT-I deficiency: Impaired Fatty Acid Oxidation

Gives Rise to Hypoglycemia, muscle weakness

Jamaican Vomiting Sickness: Deficiency of acyl-

CoA Dehydrogenase and Dicarboxylic Aciduria

Refsum disease: Phytanic Acid deposits

Zellwegers Cerebro-hepato-renal disease:

Polyenoic acid deposits

Ketosis develops Ketoacidosis


17/33

Fatty acid Synthesis

Acetyl CoA + CO2Malonyl CoAAcetyl CoA Carboxylase

CE-SH Transacetylase ATP ADP + Pi TransacetylaseACP-SH

Acetyl-S-CE + Malonyl-S ACP

Acetoacetyl ACP

Betahydroxy Butaryl ACP

Enoyl ACP

Butyryl ACP(4C)

Palmitic Acid (16C)

Synthase

Reductase

Dehydratase (x 6 cycles)

Reductase

Thioesterase

CO2

NADPH

NADP

H2O

NADPH

NADP

+ H2O

Fatty Acid Acyl Synthase Complex contains: Ketacyl synthase, A- and M-

Transacetylase, Hydratase, Reductase, ACP, Thioesterase


18/33

Fatty Acyl Synthase Complex


19/33

Diseases of Fatty Acid Biosynthesis

Linolenic acidArachidonic Acid

Omega 3, Omega 6 PUFA

Cystic fibrosis, Crohn disease,Cirrhosis, Reyessyndrome, Zellwegers Syndrome due to low

essential fatty acids


20/33

Arachidonic Acid Makes Prostaglandins

and Leukotrienes

Arachidonic Acid

Cyclooxygenase Lipooxygenase

Prostaglandins 5HPETE(with 2 double bonds)

Prostaglandins Thromboxanes LTA4LTB4

LTC4LTD4LTE4


21/33

Cholesterol and Lipoproteins

Cholesterol is steroid

Plasma Lipids are LIPOPROTEINS

Lipid Profile:Triglycerides;Lipoproteins;Cholesterol


22/33

Cholesterol

Cholesterol makes Prostenoids, Sterols, Bile Acids,

Vitamin D Complex molecules consisting of four fused carbon

rings

Cyclo-pentano-perhydro-

phenanthrene ring (CPP)Cholesterol: 3-hydroxy-5,6-cholestene


23/33

Cholesterol BiosynthesisCondensation of 2 Acetyl-CoA

HMG CoA formation

Mevalonate Formation

Isopentanyl Pyrophosphate

Geranyl Pyrophosphate

Farnesyl Pyrophosphate

Squalene

Lanosterol

Zymosterol

Desmosterol

Cholesterol

Synthase

HMG CoA Reductase

Kinase, Decarboxylase

Transferase

Transferase

Squalene Synthetase

Epoxidase

Cyclase


24/33

Cholesterol Breakdown Cholesterol makes mevalonate

CholesterolHydroxyCholesterolMevalonateHMG CoA

Cholesterol 7Hydroxylase

HMG CoA Reductase

CholesterolPregnanoloneProgesterone

17Hydroxyprogesterone Corticosterone

Cortisol Androstenedione Aldosterone

Testosterone

17 Estradiol

Estriol

Cholesterol

Cholestane 3,7,12Triol Cholestane 3,7 diolCholic Acid Chenodeoxycholic

Acid

Cholyl CoA ChenodeoxycholylCoA

Glycine Taurine

Glycocholic Tauro CDCA

Acid

Cholesterol7-DehydrocholesterolProD3

25 OH-CholecalciferolVitamin D31,24,25 Tri OH-D3


25/33

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)


26/33

Lipid Transport and Metabolism

LDL Lipoproteins: Receptors

HDL: HDL1, HDL2, HDL3 in TAG and Cholesterolmetabolism

Liver plays central role(digestion and absorption oflipids,bile,fatty acids,ketogenesis,lipoproteins)

Cholesterol + FACholesterol Esters

HMG-CoA Reductase, PPTase-I, Cholesterolhydroxylase, ACAT, LCAT, AMP Kinase

CETP, SRE-BP(Steroid Regulatory Element BP)

Apo B-48, Apo B100, Apo CII, Apo E2, Apo D


27/33

ChylomicronTAGFA; Apo-C+Apo-E help in exchange

CEC+FA

Type I-Hyperlipoproteinemia)

Endocytosis;

Lysosomal

breakdown

Type II Hyperlipoproteinemia


28/33

VLDLTAG rich; Transport TAG from liver to tissues; Apo CII TAG exchange from HDL to VLDL

B-100 favors endocytosis

CETP

Endocytosis


29/33

HDL

C o estero


30/33

C o estero

Big size

Oversize

Medium size

Oversize small size

-Apo-A1,Apo-B100,Apo-CII,Apo-E2,Apo-D

-TAG CE exchange in VLDL, HDL by CETP-ACAT, LCAT, Enzymes

-CETP, SREBP


31/33

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


32/33

Lipoprotein Transport Diseases


33/33

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 7Hydroxylase 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

TAG CE 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

Documents

Introduction to Lipid Metabolism