Metabolism of acylglycerols

and sphingolipids

Martina Srbová

Types of glycerolipids and sphingolipids

1. Triacylglycerols

function as energy reserves

adipose tissue (storage of triacylglycerol), lipoproteins

Lipogenesis - the synthesis of triacylglycerols from glucose (mainly in the liver)

Synthesis of TG

in the smooth endoplasmic reticulum

The sources of glycerol 3-phosphate:

1. the phosphorylation of glycerol (glycerol kinase)

liver

2. the reduction of dihydroxyacetone phosphate

(from glycolysis)

liver, adipose tissue

Phosphatidic acid

- the precursor for:

1. TG

2. glycerophospholipids

Dephosphorylation:

Addition of another acyl:

Formation of TG:

Synthesis, processing and

secretion of VLDL

proteins synthesized on the rough

ER are packaged with TG in the ER

and GC to form VLDL

TG, cholesterol, phospholipids and

proteins

VLDL

Fate of VLDL TG

Lipoprotein lipase

present on the lining cells of the capillaries (in adipose and sceletal muscle tissue)

coenzyme Apo C-II (from HDL)

hydrolyses TG from VLDL and chylomicrons

Storage of TG in adipose tissue

Insulin

glucose transport into cells

synthesis and secretion of LPL

Release of FA from adipose TG

↓Insulin, ↑Glucagon

intracellular cAMP increases - activates protein kinase A - phosphorylates

hormone-sensitive lipase

FA - complexes with albumin, oxidized to CO2 and water in tissues

Prolonged fasting - ketone bodies (from acetyl CoA), gluconeogenese (glycerol)

2. Glycerophospholipids

the major lipid components of biological membranes

lipoproteins, bile, lung surfactant

source of PUFA (eicosanoids)

signal transmission (hydrolysis of PIP2)

Sythesis of glycerophospholipids

Precursor: Phosphatidic acid

2 mechanisms of addition of a head group

Phosphatidic acid

2. Phospholipid interconversions:

Synthesis of glycerophospholipids

1. Phosphatidic acid - addition of a head group to the

molecule

Phospholipases

located in cell membranes or in lysosomes

Phospholipase A2 Phospholipase C

Arachidonic acid - eicosanoids Hydrolysis of PIP2 - the second messengers

Repair mechanism for membrane DAG and IP3

lipids damaged by free radicals

Degradation of glycerophospholipids

3a. Sphingomyelins

membrane components (make up 10-20% of plasma membrane lipids)

myelin

Sphingosine

3. Sphingolipids

3b. Glycolipids

the surfaces of cell membranes, receptors (hormons, cholera toxin),

specific determinats of cell-cell recognition, the antigenic determinants

of the ABO blood groups

cerebrosides, sulfatides, gangliosides

Synthesis of sphingolipids

In the Golgi complex

Formation of ceramide:

Precursors:

Serine + Palmitoyl CoA condense

to form the sphingosine

FA forms an amide with amino

group - ceramide

Degradation of sphingolipids

by lysosomal enzymes (deficienties result in lysosomal storage disease =

sphingolipidoses)

Sphingolipidoses

genetic mutations, mental retardation, death

Nemoc Deficit enzymu Kumulující lipid

Fucosidosis α-Fucosidase H-Isoantigen

Generalized gangliosidosis GM1-β-Galactosidase GM1-Ganglioside

Tay-Sachs disease Hexosaminidase A GM2-Ganglioside

Tay-Sachs variant Hexosaminid. A and B GM2-Ganglioside

Fabry disease α-Galactosidase Globotriaosylceramide

Ceramide lactoside lipidosis Ceramide lactosidase Ceramide laktoside

Metachromatic leukodystrophy Arylsulfatase A 3-Sulfogalactosylceramide

Krabbe disease β-Galactosidase Galactosylceramide

Gaucher disease β-Glucosidase Glucosylceramide

Niemann-Pick disease Sphingomyelinase Sphingomyelin

Farber disease Ceramidase Ceramide

Tay-Sachs disease

ganglioside accumulation in neurons

Regulation of lipid metabolism

Control of fatty acid synthesis

• Regulation at the level of Acetyl-CoA Carboxylase

ACC is regulated by

phosphorylation

allosteric control by local metabolites

diet: high caloric diet stimulates ACC synthesis - long term reg.

• Regulation at the level of Fatty Acid Synthase

– transcriptionally regulated

Insulin stimulates Fatty Acid Synthase expression.

Leptin inhibits Fatty Acid Synthase expression.

short-term reg.

Acetyl-CoA Carboxylase, which converts acetyl-CoA to malonyl-CoA, is the rate-limiting step of the fatty acid synthesis pathway.

The Acetyl-CoA Carboxylase is regulated by

phosphorylation

allosteric control by local metabolites.

Conformational changes associated with regulation:

In the active conformation, Acetyl-CoA Carboxylase associates to form multimeric filamentous complexes.

Transition to the inactive conformation is associated with dissociation to yield the monomeric form of the enzyme (protomer).

Control of fatty acid synthesis

Regulation at the level of ACC

Control of fatty acid synthesis

Adrenalin

Glucagon cAMP

Protein

kinase A -

AMP-Activated Kinase, a sensor of cellular energy levels, is allosterically activated by AMP, which is high in concentration when [ATP] is low.

Acetyl-CoA Carboxylase is inhibited when phosphorylated by AMP- activated kinase, leading to decreased malonyl-CoA

The decreased production of malonyl-CoA prevents energy-utilizing fatty acid synthesis when cellular energy stores are depleted.

Regulation at the level of ACC

Control of fatty acid synthesis

Adrenalin

Glucagon cAMP

Protein

kinase A -

A cAMP cascade, activated by glucagon & adrenaline when blood glucose is low, may also result in phosphorylation of Acetyl-CoA Carboxylase via Protein Kinase A.

With Acetyl-CoA Carboxylase inhibited, acetyl-CoA remains available for synthesis of ketone bodies, the alternative metabolic fuel used when blood glucose is low.

The antagonistic effect of insulin, produced when blood glucose is high, is attributed to activation of Protein Phosphatase.

Regulation at the level of ACC

Control of fatty acid synthesis

Adrenalin

Glucagon cAMP

Protein

kinase A -

Palmitoyl-CoA (product of Fatty Acid Synthase) promotes the inactive conformation, diminishing production of malonyl-CoA, the precursor of fatty acid synthesis.

This is an example of feedback inhibition.

Citrate allosterically activates Acetyl-CoA Carboxylase

[Citrate] is high when there is adequate acetyl-CoA entering Krebs Cycle.

Excess acetyl-CoA is then converted via malonyl-CoA to fatty acids for storage

Control of fatty acid degradation

1. PPAR peroxisome proliferator activated receptor

2. Energy demands of cell

3. Carnitine palmitoyl transferase I (CPT I)

Control of fatty acid degradation

1. PPAR peroxisome proliferator activated receptor

nuclear receptors act as transcription factors role in regulating the storage and degradation of dietary lipids

After binding of the ligand to receptor, these bind to DNA and initiate

transcription of genes whose products participate in β-oxidation

Ligands for PPARs:

regulate the cellular uptake of FA

activation of FA

-oxidation of FA

fatty acids C >12 , mainly 3 PUFA fibrate (drug acts on dyslipidemia)

Regulation of β-oxidation

acetyl-CoA malonyl-CoA CPT I β-oxidation

ACC

2. by energy demands of cell by the level of ATP and NADH:

FA can not be oxidized faster than NADH and FADH2 are reoxidized in the respiratory chain

3. via carnitine palmitoyl transferase I (CPT I)

CPT I is inhibited by malonyl-CoA, which is generated in the synthesis of FA by acetyl-CoA carboxylase

(ACC)

active FA synthesis inhibition of β-oxidation

Control of fatty acid degradation

Adipose tissue as an endocrine organ

Leptin

• Protein, released from

adipocytes as their TG levels

increase

• Binds to the receptors in the

hypothalamus, which leads to

the release of neuropeptides

that signal suppress appetite

• In the muscle and liver, it

stimulates FA oxidation

Adiponectin

• ↑FA oxidation by the liver and

muscle

• ↑Uptake and utilization of glucose

by the muscle

• ↓Hepatic glucose production

glucagon

epinephrine

insulin

glucagon

epinephrine

inhibition by

dephosphorylation insulin

carnitine palmitoyl

transferase I

inhibited by

phosphorylation by

AMP-activated kinase

FA metabolism is dependent upon the ratio of insulin to glucagon.

FA degradation: low insulin / glucagon ratio

FA synthesis: high insulin / glucagon ratio x

Insulin Glucagon

Activity:

Acetyl –CoA-carboxylase + - Hormone-sensitive lipase - + Synthesis:

Acetyl –CoA-carboxylase + - FA synthase + - Lipoprotein lipase + -

+ activation

- inhibition

Pictures used in the presentation:

Marks´ Basic Medical Biochemistry, A Clinical Approach, third edition, 2009 (M.

Lieberman, A.D. Marks)

Color Atlas of Biochemistry, second edition, 2005 (J. Koolman and K.H. Roehm)

Devlin, T. M. Textbook of biochemistry: with clinical correlations. 6th edition. Wiley-Liss,

2006.

Biochemistry, Voet and Voet, 4th edition 2011