lipid synthesis and degradation Flashcards
Fat: Role in biological function
• Obtained either from diet or made de novo from carbohydrates
• Play an essential role in many biological functions including:
○ Membranes
○ Uptake of lipid soluble vitamins
○ As precursors of steroid hormones
○ Energy store
§ Energy from one gram of fat = over twice that of either carbohydrate or protein
§ 1g fat-37KJ
§ 1g protein-17KJ
1g carbohydrate-16KJ
Fatty acid synthesis
• When calorific intake exceeds consumption excess is laid down as fat
• Mostly synthesised in liver however stored in adipose tissue
• However:
○ Cardiac muscle use fat as preferred energy source
○ Dietary carbohydrate is the most common source of metabolic building blocks although some amino acids can also be used Palmitic acid is the major product that is modified by enzymes to produce different fatty acids
Fatty acid strucutre
- Chains of methyl groups with terminal carboxyl group • Can have double bonds and if present, usually in cis conformation
- Humans unable to create double bonds less than position 9 Essential fatty acids obtained from diet
Fatty acid synthesis from glucose
• Occurs in cytosol
• Some citrate exported out the mitochondria and converted into acetyl CoA
○ Acetyl CoA cannot cross membrane whereas citrate can
• Acetyl CoA converted to fatty acids:
○ Some stay in liver
○ Majority imported as free fatty acids and consumed in non-hepatic tissue Majority stored in adipocytes(have ability to synthesise fats)
Transfer of acetyl CoA into the cytosol
- Pyruvate enters mitochondria and converted to oxaloacetate
- Oxaloacetate combines with Acetyl CoA to form citrate
- Citrate transported out and cleaved to form acetyl CoA and oxaloacetate
- Oxaloacetate is converted to malate and then pyruvate Acetyl CoA and NADPH formed
Citrate-malate antiport (First step)
○ Irreversible regulatory step ○ Activated by citrate
○ Inhibited by palmitic acid
○ Vitamin Biotin required
○ Acetyl CoA carboxylase inhibited by phosphorylation § Glucagon stimulates phosphorylation and therefore inhibits the enzyme ○ Expression of Acetyl CoA carboxylase increased by high carbohydrate and low fat Expression of Acetyl CoA carboxylase decreased by low carbohydrate and high fat
Citrate-malate antiport (Second step)
○ Cytosolic
○ Elongation meaning addition of 2C
a. Malonyl CoA formed by acetyl CoA carboxylase
i. Malonyl residue transferred to ACP
b. A second acetyl molecule from Acetyl CoA is then transferred to ACP where two condense to form Acetoacytyl-ACP
c. Fatty acid synthase is a multi-enzyme complex required for fatty acid synthesis
i)Exists as a dimer to make synthesis efficient as possible
Cholesterol structure
- Rigid hydrophobic molecule, virtually insoluble • Precursor of steroids, sterols and bile salts
- Transported in the circulation as cholesteryl esters
- Cannot be oxidised to O2 and H20 so provide no energy
- Important membrane component for fluidity
Cholesterol synthesis
- Synthesised mostly in ER
- Starts with activation of acetate, acetyl CoA
- Major regulatory step is the conversion of 3-hydroxyl-3-methylglutaryl CoA to mevalonate
- Cholesterol inhibits HMGCoA reductase ○ Enzyme involved in its own synthesis Difficult to reduce circulating cholesterol by diet alone as endogenous synthesis is increased
Fatty acid degradation (Mobilisation-adipocyte)
Mobilisation-adipocyte:
a. cAMP activates protein kinase A which is involved in the breakdown of glycogen and inhibition of glycogen synthesis
b. Activated protein kinase A will phosphorylate and activate triacylglycerol lipase, removing fatty acid from glycerol
c. Phosphorylated triacylglycerol lipase breaks down triacylglycerol to form diacylglycerol and transported via lipoproteins or bound to albumin.
d. One of the components, glycerol, get back to the liver as its the only part of the fatty acid which can be used to make glucose
e. Fatty acids transported to liver and activated by acyl-CoA synthase in the cytoplasm
f. Acetyl CoA produced is transported across the inner mitochondrial membrane bound to the alcohol carnitine
Fatty acid degradation (Activation)
a. Occurs in the liver cytosol b. FA activated by reacting with CoA requiring ATP
c. Transported to inner mitochondrial matrix for oxidation using carnitine
d. Carnitine deficiency causes muscle weakness or death
e. Transport inhibited by malonyl-CoA i)So large amounts of malonyl CoA prevents breakdown when excess glucose is present
Fatty acid degradation (Degradation)
a. Acyl-CoA degraded by sequential removal of 2 C units
b. As a result FADH2, NADH and acetyl-CoA are produced
c. FADH2 and NADH can be used for glycolysis This cycle continues
Fatty acid oxidation (beta-oxidation)
- FADH2 and NADH form ATP
- Acetyl CoA enters the citric acid cycle only in the presence of glycolysis
- Complete oxidation of palmitic acid give 106 molecules of ATP
- Odd chain length yield propionyl-CoA in the last round of oxidation
- Odd numbered double bonds removed by isomerase
- Even numbered bonds removed by reductase and isomerase Acetly-CoA in hepatocytes converted to ketone bodies and are transported to non hepatic tissue for metabolism
Ketogenisis
- Acetyl-CoA converted to acetoacetyl-CoA
- Acetoacetyl-CoA converted to HMG-CoA (β-hydroxyl β methylglutaryl-CoA)
- HMG-CoA converted to acetoacetate
- Acetoacetate can be reduced to 3-β-hydroxybuterate or non-enzymatically to acetone Ketogenisis high when ration of insulin/glucagon is low as this inhibits acetly-CoA carboxylase
Fate of Ketone bodies
• Major energy source for cardiac muscle and renal cortex
○ Dependent on the flow of carbohydrate in glycolysis During starvation up to 75% of the brains energy is derived from acetoacetate.
