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Chapter 8. Metabolism of lipid. Cai danzhao. Lipids are substances that are insoluble in water but soluble in organic solvents. Including: Fats (triglycerides , t riacylglycerols , TAG ) Function : store and supply energy phospholipids
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Chapter 8 Metabolism of lipid Cai danzhao
Lipids are substances that are insoluble in water but soluble in organic solvents. • Including: Fats (triglycerides,triacylglycerols,TAG) Function: store and supply energy phospholipids Lipoids cholesterol and cholesterol ester glycolipids Function: as membrane compounds
Cholesterol (ch) Fatty acid Triglyceride(TAG) Phospholipid(PL) Cholesterol ester (CE)
Carboxyl Hydrocarbon chain unsaturated FA (one double bonds) Saturated FA
Nomenclature: the chain length number of double bonds Palmitic acid 16:0 Oleic acid 18:1(Δ9)
Section 8.1 Digestion and Absorption of Lipids
Digestion of Lipids • Location: duodenum, small intestine • Condition: 1. bile salts (emulsification) 2. lipolytic enzymes Pancreatic lipase Phospholipase A2 Cholesterol esterase
Process bile salts food lipids small particles pancreatic lipase triglyceride 2-monoacylglycerol + 2FFA phospholipase A2 phospholipid lysophosphatide + FFA cholesterol esterase cholesterol ester cholesterol + FFA
Pancreatic colipase • Pancreatic colipse is the necessary cofactor of pancreatic lipase. • Excreted by pancreatic acinar cells as a proenzyme, which activated in the small intestine. • Can anchor the lipase to the surface of lipid micelles. • Assist lipase in two ways: 1.enhances the lipase activity 2.against the inhibitory effects of bile salts and surface denaturation.
Absorption of lipids • Medium and short chain fatty acid (10Cs or less) TAG emulsification absorption intestine mucosal cells degradation FFA and glycerol transport portal vein blood circulation
Long chain fatty acids (12-26C) + monoacylglycerol absorbed synthesis epithelial cells TAG + lipoproteins • lysophosphatide + FFA CM absorbed synthesis (chylomicron) epithelial cells PL • cholesterol + FFA lymphatic system absorbed synthesis epithelial cells CE blood circulation
Acyl CoA synthetase CoA + RCOOH RCOCoA ATP AMP PPi Acyl CoA transferase Acyl CoA transferase R2COCoA CoA R3COCoA CoA TAG synthesis in epithelial cells:monoacylglycerolpathway monoacylglycerol 1,2-diacylglycerol TAG
Section 8.2 Metabolism of Triacylglycerols
Degradation of TAG glycerol FA
Lipolysis: also named fat mobilization, is a process breaking down the fat (TAG) stored in adipose tissue and liberating the glycerol and FFAs from which into the blood circulation. • Key enzyme: TAG lipase (hormone sensitive lipase, HSL)
Lipolytic hormones: stimulate TAG hydrolysis Glucagons, Adrenocorticotropic hormone (ATCH) epinephrine norepinephrine • Anti-lipolytic hormones: stimulate TAG formation insulin prostaglandin E2 nicotinic acid
H2O FA H2O FA H2O FA TAGDAG MAG Glycerol TAG lipase a DAG lipase MAG lipase TAG lipase a ADP + Pi TAG lipase b ATP cAMP dependent protein kinase ATP cAMP 5’-AMP Adenylate cyclase Phosphodiesterase lipolytic hormones (Epinephrine ) anti-lipolytic hormones (insulin)
FFA +plasma albumins fatty acid- transport albumin complexes all the body glycerokinase • Glycerol glycerol-3-phosphate dihydroxyacetone phosphate glucose metabolism Notation: adipose cells and skeletal muscles lack glycerokinase, can not use glycerol well
β-Oxidation of Fatty acids • FAs are the major energy source of human the biologically available energy in TAGs: ~ 95 % in their 3 long-chain FAs ~ 5% in their glycerol Oxidation location: in the cytoplasm and mitochondria of most body cells (except those of the brain and intestine)
The process of FA degradation • Activation • Transport into mitochondria • β-oxidation • Acetyl CoA utilization into citric acid cycle change to ketone bodies into other metabolic pathway
+ CoA-SH 1.Activation of FA Activation of FA takes place on the outer mitochondrial membrane (in cytoplasm) Acyl CoA synthase Acyl-CoA Fatty acid ATP AMP+PPi
2.Transport of Acyl CoA into mitochondria key enzyme: carnitine acyltransferase I translocase
3. β-oxidation of Acyl CoA • In mitochondrial matrix,successive 2-Cunits are removed from the carboxyl end ofthe fatty acyl chain in the form of acetyl-CoAby a repeated sequence of 4 reactions, and the oxidation process take place at the β-carbon.
To Palmitoyl CoA (C16): 1.Dehydrogenation (FAD) 2.Hydration 3.Dehydrogenation (NAD+)
4.Thiolysis Result of a round of β-oxidation: 1NADH, 1FADH2, 1Acytyl CoA, 1Acyl CoA (Cn-2)
1 2 3 4 5 6 7 C16 Acetyl -CoA Acyl CoA (Cn-2) can now go through anotherset of β-oxidationreactions
1 molecule of palmitoyl-CoA will pass through the sequence 7 times, eventually be oxidized to: 8 Acetyl CoAs 7 NADHs 7 FADH2s
ATP produced during oxidation of palmitate 2.67 Glucose (C16): 85.3 ATP
Alternative Oxidation Pathway of Fatty Acids oleic acid (18:1, Δ9): Can produce a cis-Δ3 C12 acyl CoA, but β-oxidationacts only on trans double bonds. • 1.Unsaturated FA Enoyl-CoA isomerase: make a trans- Δ2 C12 acyl CoA, then β-oxidationcancontinue
2,4-dienoyl-CoA reductase Can convert cis- Δ4double bond to trans- Δ3,
2.Peroxisomal Fatty Acid Oxidation • for very long chain FA digestion.(C20、C22) • No ATP produced. • FA reduced in length by this pathway will be transferred to mitochondria for further oxidation. very long chain FA(C20、C22) (peroxisomal) (mitochondria) Acyl-CoA oxidase (FAD) chain shorted FA βOxidation
3.Propionyl CoA • β-oxidation of the odd-chain fatty acids, which are relatively rare in nature, produce a propionyl CoA in the final round. carboxylase Succinyl CoA CH3CH2CO~CoA Citric acid cycle
Ketone Bodies Formation and Utilization • Ketone Bodies are acetoacetate (30%) β-hydroxybutyrate (70%) acetone • Generated in liver cells (mitochondria), used by extrahepatic tissues (mitochondria also). • Precursor: Acetyl CoA
CO2 Ketogenesis HMGCoA synthase Acetoacetyl CoA CoASH CoASH 3-hydroxy-3-methylglutaryl CoA NADH+H+ NAD+ β-hydroxybutyrate acetoacetate acetone
Utilization of ketone bodies (cardiac, kidney, brain, skeletal muscles) β-hydroxybutyrate NAD+ NADH+H+ Succinyl CoA CoASH+ATP acetoacetate succinate PPi+AMP Acetoacetyl CoA CoASH
Physiological significance of ketogenesis • A way by which liver transfer fuel to extrahepatic tissues (prolonged starvation), ketone bodies can replace glucose as the major source of energy, especially for brain. • The normal concentration of ketone bodies in blood is very low. ﹤0.5mmol/L
Under starveling condition, ketogenesis is accelerated. • Under some pathological condition (such as diabetes), the synthesis is faster than utilization, so the concentration of ketone bodies in the blood is high, (up to 20mmol/L), which is called ketonemia , • ifthe concentration is too high to be excreted in the urine, that is ketonuria.
Ketone bodies are acidic compounds, the accumulate of which in the blood will decreasethe pHof blood , causeketoacidosis.
Regulation of ketogenesis • 1.Feeding status: hungry state: lipolytic hormones (glucagon) FA oxidation ketogenesis lipolysis FFA Feeding state FA oxidation ketogenesis insulin lipolysis FFA
2.Metabolism of glycogen in the hepatic cells Sufficient glucose supply: FFA triacylglycerols Glucose deficiency: β- Oxidation ketogenesis FFA
3.Malonyl CoA concentration Malonyl CoA can inhibit carnitine acyltransferase Ⅰ. malonyl CoA transportion of fatty acids into mitochondria β- Oxidation and ketogenesis
8.2.2 FA Biosynthesis • FA synthesis is not the reverse of degradation: different pathways,enzymes, location of cells • Location of FA synthesis: cytoplasm of liver (major), adipose and other tissue cells. • First step: synthesis of palmitic acid
Palmitic Acid Biosynthesis Material: • acetyl CoA (come mostly from glucose) • NADPH (pentose phosphate pathway or produced by malate enzyme.) • ATP • HCO3-
ATP-citrate lyase MITOCHONDRIA CYTOSOL Acetyl CoA • Acetyl CoA must be transport to cytosol. ATP Acetyl CoA citrate citrate Citrate synthase oxaloacetate oxaloacetate malate pyruvate pyruvate citrate pyruvate cycle Inner membrane
Formation of malonyl CoA ATP + Acetyl CoA + HCO2-Malonyl CoA + ADP + Pi acetyl CoA carboxylase biotinact as CO2 carrier
Acetyl CoA carboxylaseis the key enzyme of the FA synthesis. • Allosteric regulation: up-regulate: citrate and isocitrate down-regulate: palmitoyl CoA • Phosphorylation regulation up-regulate: dephosphorylation (insulin) down-regulate: phosphorylation (glucogen)
Repetivity steps catalyzed by Fatty Acid Synthase CH3COSCoA + 7 HOOCH2COSCoA + 14NADPH+H+ CH3(CH2)14COOH + 7 CO2+ 6H2O + 8HSCoA+ 14NADP+ • The chain of FA grows 2-carbons per cycle. • The reactions are similar to the reversal of FA β-oxidation.
Fatty Acid Synthase In E.coli (becteria): Fatty acid synthase system (TypeⅡ system) contain 7 enzymes organized into a cluster. • In mammalian: Fatty acid synthase (Type Ⅰsynthase) is a single multifunctional polypeptide with 7 activities.
The acyl carrier protein (ACP) carries a growing fatty acyl chain from one active site to the next.
Process : 1.Charging β-ketoacyl-ACP synthase (KS) with an acetyl group