Metabolism of acylglycerols and sphingolipids Alice Skoumalová

Types of glycerolipids and sphingolipids

1.Triacylglycerols  function as energy reserves  adipose tissue (storage of triacylglycerol), lipoproteins

2. Glycerophospholipids  the major lipid components of biological membranes  lipoproteins, bile, lung surfactant  source of PUFA (eicosanoids)  signal transmission (hydrolysis of PIP 2 )

3. Plasmalogens  myelin, heart muscle PAF (Platelet-activating factor)  released from phagocytic blood cells in respons to varios stimuli (platelet aggregation, edema, hypotension)

4. Sphingomyelins (sphingophospholipids)  membrane components (make up 10-20% of plasma membrane lipids)  myelin Sphingosine

4. 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

FA (from the diet, synthetized)  TG  glycerophospholipides  sphingolipides 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

Lipoproteins Function:  Lipid transport (cholesterol, cholesterol esters, triacylglycerols, phospholipids) Structure: A nucleus: triacylglycerols, cholesterol esters A shell: phospholipids, apoproteins, cholesterol

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 CO 2 and water in tissues Prolonged fasting - ketone bodies (from acetyl CoA), gluconeogenese (glycerol)

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 A2Phospholipase C Arachidonic acid - eicosanoidsHydrolysis of PIP 2 - the second messengers Repair mechanism for membraneDAG and inositol PIP 2 lipids damaged by free radicals Degradation of glycerophospholipids

Synthesis of sphingolipids In the Golgi complex (membranes of SV) Formation of ceramide: Precursors: Serine + Palmitoyl CoA condense

Degradation of sphingolipids  by lysosomal enzymes (deficienties result in lysosomal storage disease = sphingolipidoses) Sphingolipidoses genetic mutations, mental retardation, death NemocDeficit enzymuKumulující lipid Fucosidosisα-FucosidaseH-Isoantigen Generalized gangliosidosisG M1 -β-GalactosidaseG M1 -Ganglioside Tay-Sachs diseaseHexosaminidase AG M2 -Ganglioside Tay-Sachs variantHexosaminid. A and BG M2 -Ganglioside Fabry diseaseα-GalactosidaseGlobotriaosylceramide Ceramide lactoside lipidosisCeramide lactosidaseCeramide laktoside Metachromatic leukodystrophyArylsulfatase A3-Sulfogalactosylceramide Krabbe diseaseβ-GalactosidaseGalactosylceramide Gaucher diseaseβ-GlucosidaseGlucosylceramide Niemann-Pick diseaseSphingomyelinaseSphingomyelin Farber diseaseCeramidaseCeramide

Tay-Sachs disease  ganglioside accumulation in neurons

Summary Triacylglycerols (synthesis) Storage of TG in adipose tissue Release of FA from adipose tissue Glycerophospholipids (synthesis, degradation) Sphingolipids (synthesis, degradation)

Pictures used in the presentation: Marks´ Basic Medical Biochemistry, A Clinical Approach, third edition, 2009 (M. Lieberman, A.D. Marks)