Dr. Lucie karydov, Ph.D.

A group of heterogenous substances Insolubility in water! The importance of lipids:

Source of energy Products of lipid metabolism important substrates for other metabolic pathways! A part of biomembranes cytoplazmatic m., subcellular membranes Precursors of vitamins, hormones

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Triacylglycerols degradation, synthesis, regulation Fatty acids degradation, regulation Ketone bodies Fatty acids biosynthesis, regulation Complex lipids Cholestrol biosynthesis, regulation Review of lipids

TAG = triglycerides, neutral lipids Esters of a glycerol and fatty acids

The major source of energy for the body

Provide twice more energy than other nutrients
H, kJ/g of dry basis carbohydrate lipid protein 16 37 17

Adipose tissue
Adipocytes

Dietary lipids (mainly TAG, also PL, cholesterol) Digestion of lipids (lectures in physiology!)
Mainly in a small intestine Duodenum
Emulsification (bile acids from gallblader) micelles Pancreatic lipase

Jejunum absorption Transport to tissues chylomicrons

Lipoprotein lipase in capillaries Tissues storage x utilization!

Mobilization of stored fats

o

a fasting, intensive physical exercise, adaptation to a stress Hormone-sensitive lipase (HSL)

Hydrolysis of TAG in adipose tissue release of glycerol + fatty acids to blood Important adaptation to stress!!! Epinephrine and glucagon increase of HSL activity!

The activation of HSL by hormones

Epinephrine, glucagon - activity, insulin - activity

o Fatty acids a source of energy mainly for myocardium and muscles

Liv er, kidney! low activity in adipose tissue

o Glycerol a source of glucose during fasting!

Synthesis of TAG

Predominantly in liver and adipose tissue Glycerol-3-phosphate (dihydroxyaceton phosphate) Activated fatty acids (acyl-CoA)

Glycerol phosphate in adipose tissue only from glucose (low activity of glycerol kinase)!

Regulation of TAG metabolism

Nutrition state of organism

Good supply of food utilization of glucose lipogenesis (fat storage)

Low concentration of free fatty acids in blood

Fasting, food with high TAG inhibition of lipogenesis, activation of lipolysis

High concetration of free fatty acids in blood

Hormones

Insulin activation of phosphodiesterase - cAMP dephosphorylation of HSL - activity - fatty acids in blood - lipogenesis Epinephrine, glucagon activation HSL - lipolysis

Summary of TAG:
Esters of a glycerol and fatty acids o Major source of energy in organism o The main type of fat in food o Hormone-sensitive lipase adaptation to stress!!!
o

Metabolism of lipids is affected by nutrition state of organism and hormones!

Mainly in the form of esters Even number of C (mainly 16-20 C)

Saturated FA without double bonds

Unsaturated FA double bonds cis conformation!

Stearic acid (18:0)

Palmitooleic acid (16:1(9))

Essential FA linoleic a., -linolenic a.

Inability to synthesize them supply from food!

Arachidonic acid 20:4 (5,8,11,14) prostaglandins, leukotriens and tromboxans (inflammatory mediators)

Oxidation of fatty acids

o

The main catabolic route of FA

Progressive elimination of two carbon fragments from FA Products - acetyl-CoA , FADH2, NADH+H+ Production of a high amount of ATP

Mitochondrial pathway Only in the presence of O2 Consist of several steps:

Activation of FA Transport of FA to mitochondria -oxidation of FA

Activation of fatty acids

o
o

Take place in cytosol Delivery of energy (ATP) is required!!!

Both high-energy ATP bonds are utilized!

Transport of FA to mitochondrial matrix

o

Inner membrane is impermeable for Acyl-CoA specialized carrier is required carnitine

o

Carnitine obtained from diet (mainly meat product) and synthetized in the body

Steps of translocation

-oxidation
Occurs in mitochondrial matrix Cyclic repetition of 4 reactions:

Dehydrogenation (FAD) a double bond formation Hydratation of the double bond 3-L-hydroxyacyl-CoA Dehydrogenation (NAD+) -ketoacyl-CoA Thiolysis cleavage of the bond between C-C

One cycle 2C shortening of acyl chain

Acetyl-CoA molecule is formed in every cycle

Oxidation of FA high energy yield! Every cycle FADH2, NADH+H+, acetyl-CoA

FADH2, NADH+H+ respiratory chain 2; 3 ATP Acetyl-CoA citric acid cycle 12 ATP 2 ATP for activation

Total oxidation of palmitoic acid (16C)

Oxidation of FA with an even number of C

Products acetyl-CoA
Products acetyl-CoA + propionyl-CoA (3C)
O
CO2 ATP ADP+Pi

Oxidation of FA with an odd number of C

H OOC C CH3 (S)-metylmalonyl-COA O C SCoA

metylmalonyl CoA racemase

O C
-

H3C

CH2

SCoA
propionyl CoA carboxylase

H3C

SCoA

propionyl-CoA

COO (R)-metylmalonyl-CoA
methylmalonyl mutase

O
-

OOC CH2 C

SCoA

sukcinyl-CoA

citric acid cycle

Special types of -oxidation

-oxidation of unsaturated FA modified

Provides less energy Normal -oxidation to a double bond isomerization of cis to trans configuration normal -oxidation

Peroxizomal -oxidation

Very-long-chain FA (> 22C) Shortened in peroxisomes (to octanoyl-CoA) Diffusion to mitochondial matrix normal -oxidation

Exist also - and -oxidation of FA rare!

Regulation of -oxidation

Hormone-sensitive lipase (HSL)

Delivery of substrates Degradation of TAG v adipocytes release of MK epinephrine, glucagon adaptation to stress insulin Low activity after food Inhibition of high concentration of malonyl-CoA an indicator of the FA synthesis in cytosol Inhibition of acetyl-CoA

Carnitine acyltransferase I

Thiolase

The fate of acetyl-CoA in the organism

Source of energy

Physiological conditions citric acid cycle Excess (fasting, diabetes mellitus) ketone bodies

Precursor

FA TAG, complex lipids Cholesterol steroid hormones, vitamins, bile acids

Summary of degradation of FA:

Oxidation of FA consist of 3 steps activation, transport, -oxidation o -oxidation a cyclic repetition of 4 steps o Products - acetyl-CoA, FADH2, NADH+H+
o o

Significance:

Energy Product acetyl-CoA an important substrate for other metabolic route

An alternative fuel for cells Ketogenesis conversion acetyl-CoA (product of FA oxidation) to ketone bodies

Produced in liver mitochondia Ketone bodies - water soluble equivalents of FA

Why ketone bodies are produced?

Acetyl-CoA

Citric acid cycle Ketogenesis

Green - during fasting

Fasting

ketone bodies are an important source of energy for tissues (also brain)!!!

Synthesis of ketone bodies

2x acetyl CoA
thiolase

Only in liver mitochondria

H3C

CoASH O

O C CH2

C H2O

SCoA acetacetyl-CoA

HMG CoA synthase

acetyl CoA CoAsH

OH
-

O CH2

OOC

CH2

C CH3

C SCoA 3-hydroxy 3-metylglutaryl-CoA (HMG-CoA)

HMG CoA lyase

acetyl-CoA

O H3C NADH+H ++ NAD+ H H3C C OH CH2 COO

-

CH2 COO- acetoacetate

spontaneously

3-hydroxybutyrate dehydrogenase

O H3C C CH3 acetone

3-hydroxybutyrate

Utilization of ketone bodies

Ketone bodies are acids production acidosis (typical state - diabettes mellitus)

Summary of ketone bodies

Acetoacetate, aceton, 3-hydroxybutyrate Important source of energy during fasting

Peripheral tissues utilization in citric acid cycle Hard fasting source of energy for brain (physiological source of energy only glucose!)

Ketoacidosis typical for diabettes mellitus