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 VLDL TG, cholesterol, phospholipids and proteins
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. Glycerophospholipids the major lipid components of biological membranes lipoproteins, bile, lung surfactant source of PUFA (eicosanoids) signal transmission (hydrolysis of PIP 2 )
Sythesis of glycerophospholipids Precursor: Phosphatidic acid Phosphatidic acid 2 mechanisms of addition of a head group
Synthesis of glycerophospholipids 1. Phosphatidic acid - addition of a head group to the molecule 2. Phospholipid interconversions:
Degradation of glycerophospholipids Phospholipases located in cell membranes or in lysosomes Phospholipase A2 Arachidonic acid - eicosanoids Phospholipase C Hydrolysis of PIP 2 - the second messengers Repair mechanism for membrane DAG and IP 3 lipids damaged by free radicals
3. Sphingolipids Sphingosine 3a. Sphingomyelins membrane components (make up 10-20% of plasma membrane lipids) myelin
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 G M1 -β-galactosidase G M1 -Ganglioside Tay-Sachs disease Hexosaminidase A G M2 -Ganglioside Tay-Sachs variant Hexosaminid. A and B G M2 -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 short-term reg. 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.
Control of fatty acid synthesis 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 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.
Control of fatty acid synthesis Regulation at the level of ACC 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. Adrenalin Glucagon camp Protein kinase A - The antagonistic effect of insulin, produced when blood glucose is high, is attributed to activation of Protein Phosphatase.
Control of fatty acid synthesis Regulation at the level of ACC 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. Adrenalin Glucagon camp Protein kinase A - 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: fatty acids C >12, mainly 3 PUFA fibrate (drug acts on dyslipidemia) regulate the cellular uptake of FA activation of FA -oxidation of FA
Control of fatty acid degradation Regulation of β-oxidation 2. by energy demands of cell by the level of ATP and NADH: FA can not be oxidized faster than NADH and FADH 2 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 acetyl-coa malonyl-coa CPT I β-oxidation ACC
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 inhibited by phosphorylation by AMP-activated kinase carnitine palmitoyl transferase I glucagon epinephrine inhibition by dephosphorylation insulin
Activity: Insulin Glucagon Acetyl CoA-carboxylase + - Hormone-sensitive lipase - + Synthesis: Acetyl CoA-carboxylase + - FA synthase + - Lipoprotein lipase + - + activation - inhibition FA metabolism is dependent upon the ratio of insulin to glucagon. FA degradation: low insulin / glucagon ratio FA synthesis: high insulin / glucagon ratio x
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