Fatty Acids & Triglycerides Notes 2nd Stage Biochemistry PDF

Biochemistry 2nd stage Dr.Lamees Majid Al-Janabi FATTY ACIDS ILO:K2,S11,A0. Objectives: The students are learned to understand the SYNTHESIS OF THE FATTY ACIDS including the following points: -Transpor...

Biochemistry 2nd stage Dr.Lamees Majid Al-Janabi FATTY ACIDS ILO:K2,S11,A0. Objectives: The students are learned to understand the SYNTHESIS OF THE FATTY ACIDS including the following points: -Transportation of acetyl CoA. -Formation of malonyl CoA. -Fatty acid synthase multienzyme complex - Elongation and Desaturation of the fatty acids chain -regulation of fatty acid synthesis SYNTHESIS OF FATTY ACIDS De+nition: De#ned as synthesis of palmitate from acetyl- CoA in the cytosol. Site: Liver, kidney, brain, mammary gland, adipose tissue. Cellular site: Cytosol. Coenzymes/cofactors: NADPH (from HMP shunt), ATP, manganese, biotin, HCO3-. Starting material: Acetyl-CoA. The primary metabolic substrate for synthesis of fatty acid is Acetyl CoA which is generated from the oxidation of pyruvate, and by the catabolism of fatty acids, ketone bodies, and certain amino acids. Acetyl Co A from catabolic reaction is generated mainly in the mitochondria. Whereas the fatty acid synthesis occur in the cytoplasm therefore we need a special transport mechanism for transportation of acetyl Co A from the mitochondria to the cytoplasm because the CoA portion of acetyl Co A cannot cross the mitochondrial membrane. The acetyl Co A will react with oxaloacetate (OA) to form the citrate by the enzyme citrate synthetase. The citrate then will pass the 1 mitochondrial membrane to the cytoplasm where it react with CoA to form acetyl CoA & this step need 1 ATP. Transport of acetyl-CoA from mitochondria to cytosol (1 = pyruvate dehydrogenase; 2 = citrate synthase) Production of cytosolic acetyl CoA Formation of malonyl CoA It is the rate limiting step catalyzed by the allosteric enzyme acetyl CoA Carboxylase which is allosterically stimulated by citrate and inhibited by long chain fatty acyl CoA. Biosynthesis of malonyl-CoA 2  Adrenalin will reduce the formation of fatty acid , while the insulin will increase the formation of fatty acid. Fatty acid synthase: a multifunctional enzyme in eukaryotes The remaining series of reactions of fatty acid synthesis in eukaryotes is catalyzed by the multifunctional, dimeric enzyme, fatty acid synthase. Fatty acid synthase complex which is a dimer with seven enzymes and acyl carrier protein on each subunit. Synthesis of palmitate 3 Interrelationship between glucose metabolism and palmitate synthesis 4 DESATURATION OF THE CHAIN Animals can synthesis fatty acid contain only one unsaturated bond between C9 &C10.Desaturation of the chain : the cell of the liver and the adipose tissue contain the necessary enzyme for conversion of palmitoyl –SCoA and stearoyl –SCoA to the respected unsaturated palmitoleyl – SCoA and oleyl-SCoA (these enzymes called mix function oxidases). This reaction occur in the E.R and cytoplasm ,in mammals this enzyme system can only desaturate the fatty acid with double bond between C9- C10 ,therefore, mammals are unable to synthesize polyunsaturated (essential F.A). -Regulation of lipogenesis:- 1. The nutritional state of the organism is the main factor regulating the rate of lipogenesis. The rate is high in the well-fed animal whose diet contains a high proportion of carbohydrate. It is depressed under conditions of restricted caloric intake, on a fat diet, or when there is a deficiency of insulin, as in diabetes mellitus. 2. Acetyl co A carboxylase:- is an allosteric enzyme and is the most important enzyme in the regulation of lipogenesis and is activated by citrate. 3. Pyruvate dehydrogenase:- Acyl co A causes an inhibition of pyruvate dehydrogenase. 4. Insulin:- stimulates lipogenesis by increasing acetyl-co A carboxylase activity. It increases the transport of glucose into the cell (e.g. adipose tissue), increasing the availability of both pyruvate for fatty acid synthesis and glycerol 3-phosphate for esterification of the newly formed fatty acid. 5  Biochemistry 2nd stage Dr.Lamees Majid Al-Janabi TRIGLYCERIDES ILO:K2,S11,A0. Objectives: The students are learned to understand the Triglycerides metabolism including the following points: -Synthesis of Triglycerides - Source of glycerol -3-Phosphate - Hormonal Regulation of Triglycerides Degradation in Adipose tissue SYNTHESIS OF TRIGLYCERIDES fatty acids stored as components of triacylglycerol. Monoacylglycerol, diacylglycerol, &triacylclycerol formerly called Glycerides. e.g. Triglyceride consist of one, two, or three molecules of fatty acid. -Synthesis:- Liver and adipose tissue are the major sites of triacylglycerol (TAG) synthesis. The TAG synthesis in adipose tissue is for storage of energy whereas in liver it is mainly secreted as VLDL and is transported to peripheral tissues. The TAG is synthesised by esterification of fatty acyl CoA with either glycerol-3-phosphate or dihydroxy acetone phosphate (DHAP) 1  Pathways for production of glycerol phosphate in liver and adipose tissue Note:- a- Adipocyte can take up glucose only in the presence of the hormone insulin. Thus, when plasma glucose—and, therefore, plasma insulin—levels are low, adipocytes have only a limited ability to synthesize glycerol phosphate, and cannot produce TAG.] b- A fatty acid must be converted to its activated form (attach to co enzyme A) before it can participate in triacylglycerol synthesis. 2  Synthesis of triacylglycerol Typically the fatty acid on carbon no.1 is saturated and on carbon no.2 is typically unsaturated and the fatty acid on carbon no.3 could be the either.So the type of the fatty acid on carbon no.3 usually determine the melting point of TG. 3  METABOLISM OF ADIPOSE TISSUE The adipose tissue serves as a storage site for excess calories ingested. The triglycerides stored in the adipose tissue are not inert. They undergo a daily turnover with new triacylglycerol molecules being synthesized and a definite fraction being broken down. Adipose Tissue in Well-fed Condition i. Under well-fed conditions, active lipogenesis occurs in the adipose tissue. ii. The dietary triglycerides transported by chylomicrons and the endogenously synthesized triglycerides from liver brought by VLDL are both taken up by adipose tissue and esterified and stored as TAG. iii. In well-fed condition, glucose and insulin levels are increased. The stimulant effect of insulin on the uptake of glucose by adipose tissue, on iv. the glycolysis and on the utilisation of glucose by HMP pathway also enhances lipogenesis. v. Insulin also causes inhibition of hormone sensitive lipase, and so lipolysis is decreased. Adipose Tissue in Fasting Condition i. TAG from the adipose tissue is mobilised under the effect of the hormones, glucagon and epinephrine. ii. The intracellular hormone sensitive lipase is enhanced ,which acts on TAG and liberates fatty acids. iii. Under conditions of starvation, a high glucagon, ACTH, glucocorticoids and thyroxine have lipolytic effect. The released free fatty acids (FFA) are taken up by peripheral tissues as a fuel. Well-fed state During fasting Lipogenesis increased Lipogenesis inhibited Lipolysis inhibited Lipolysis increased Lipoprotein lipase active Glucagon activates Insulin inhibits HS-lipase HS-lipase FFA in blood increased Adipose Tissue and Diabetes Mellitus 4 i. Lipolysis is enhanced and high FFA level in plasma is noticed in diabetes mellitus. ii. The insulin receptors on the cell surface of adipocytes are decreased, leading to insulin insensitivity in diabetes. iii. In type 2 diabetes mellitus, there is insulin resistance and Hepatic gluconeogenesis occurs uninhibited leading to hyperglycemia. iv. Increased mobilization of fatty acids from adipose tissue and the persistently high free fatty acid levels in the presence of hyperinsulinemia stimulate synthesis of triacyl glycerol. v. The overproduction of TAG leads to increased release of VLDL from liver causing hypertriglyceridemia. vi. The excess deposition of TAG in adipose tissue accounts for the obesity prevalent in type 2 diabetes patients. Adipose Tissue and Obesity i. The fat content of the adipose tissue can increase to unlimited amounts, depending on the amount of excess calories taken in. This leads to obesity. ii. Plasma insulin level is high. But the insulin receptors are decreased; and there is peripheral resistance against insulin action. iii. When fat droplets are overloaded, the nucleus of adipose tissue cell is degraded, cell is destroyed, and TAG becomes extracellular. Such TAG cannot be metabolically reutilised and forms the dead bulk in obese individuals. Hormonal regulation of triacylglycerol degradation in the adipocyte 5  Fate of glycerol: The glycerol released during TAG degradation cannot be metabolized by adipocytes because they apparently lack glycerol kinase. Rather, glycerol is transported through the blood to the liver, where it can be phosphorylated. The resulting glycerol phosphate can be used to form TAG in the liver, or can be converted to DHAP by reversal of the glycerol phosphate dehydrogenase reaction. DHAP can participate in glycolysis or gluconeogenesis.  Fate of fatty acids: The free (unesterified) fatty acids move through the cell membrane of the adipocyte, and immediately bind to albumin in the plasma. They are transported to the tissues, where the fatty acids enter cells, get activated to their CoA derivatives, and are oxidized for energy. 6