Chapter 5 Metabolism of Lipids The biochemistry and molecular biology department of CMU
Concept • Lipids are substances that are insoluble or immiscible in water, but soluble in organic solvents.
Fats (Triglyceride or triacylglycerole) To store and supply energy Lipids Phospholipids To be important membrane components Glycolipids Lipoids Cholesterol Cholesterol ester
Contents Section 1 Fatty acids Section 2 Metabolism of Triglycerids Section 3 Metabolism of Phospholipids Section 4 Metabolism of Cholesterols Section 5 Metabolism of Plasma Lipoproteins
Essential Fatty Acids (EFA) • Linoleic,linolenic and arachidonic acids are called essential fatty acids, because they cannot be synthesized by the body and must be obtained through diet.
§1.2 Important Derivatives of Arachidonic acids Arachidonic acids (AA) in turn gives rise to biologically important substances known as the eicosanoids. • Prostaglandins (PGs) • Thromboxanes (TXs) • Leukotrienes (LTs)
§ 2.1 Degradation of TG § 2.1.1 Fat catabolism (lipolysis) § 2.1.2 β-Oxidation of Fatty acids § 2.1.3 Other Oxidations of Fatty acids § 2.1.4 Ketone Bodies Formation and Utilization
§ 2.1.1 Fat catabolism (lipolysis) Fat mobilization： The triacylglycerol stored in the adipocytes are hydrolyzed by lipases, to produce free fatty acids (FFA) and glycerol, which are released to the blood, this process is called fat mobilization.
The fatty acids thus released diffusively from the adipocyte into the blood, where they bind to the serum albumin.
Hormone sensitive lipase (HSL) • TG lipase is the rate-limiting enzyme in the TG degradation in adipose tissue. It is also named HSL because it is regulated by some hormones.
Effect of hormones on lipolysis • Lipolytic Hormones: epinephrine norepinephrine adrenocorticotropic hormone (ACTH) thyroid stimulating hormone (TSH) Glucagon etc. • Antilipolytic Hormones: insulin
glycerol metabolism Place: liver, kidney, intestine
Note • In muscle cells and adipocytes, the activity of glycerol kinase is low, so these tissues cannot use glycerol as fuel.
§ 2.1.2 β-Oxidation of Fatty acids • Fatty acids are one of the main energy materials of human and other mammalian. • Fatty acid catabolism can be subdivided into 3 stages.
Stage 1 Activation of FAs • Acyl-CoA Synthetase (Thiokinase), which locates on the cytoplasm, catalyzes the activation of long chain fatty acids.
Key points of FA activation 1. Irreversible 2. Consume 2 ~P 3. Site: cytosol
Stage 2Transport of acyl CoA into the mitochondria ( rate-limiting step) • Carrier:carnitine
Rate-limiting enzyme • carnitine acyltransferase Ⅰ
Stage 3: β-oxidation of FAs β-oxidation means β-C reaction. Four steps in one round step 1:Dehydrogenate step 2:Hydration step 3:Dehydrogenate step 4:Thiolytic cleavage
Summary one cycle of the β-oxidation: fatty acyl-CoA + FAD + NAD+ + HS-CoA→fatty acyl-CoA (2 C less) + FADH2 + NADH + H+ + acetyl-CoA
The product of the β-oxidation is in the form of FADH2, NADH, acetyl CoA, only after Krebs cycle and oxidative phosphorylation, can ATP be produced.
Energy yield from one molecule of palmitic acid The net ATP production: 131－2 = 129
§ 2.1.3 Other Oxidations of Fatty acids 1. Oxidation of unsaturated fatty acids 2. Peroxisomal fatty acid oxidation 3. Oxidation of propionyl-CoA
1. Oxidation of unsaturated fatty acid • Mitochondria • Isomerase: cis→ trans • Epimerase: D (-) →L (+)
2. Peroxisomal fatty acid oxidation Very long chain fatty acids FAD Acyl-CoA oxidase shorter chain fatty acids β-oxidation
3. Oxidation of propionyl-CoA propionyl-CoA Carboxylase (biotin) Epimerase Mutase (VB12) succinyl-CoA
§ 2.1.4 Ketone Bodies Formation and Utilization • Ketone bodies arewater-soluble fuels normally exported by the liver but overproduced during fasting or in untreated diabetes mellitus, including acetoacetate, β-hydroxybutyrate, and acetone.
The formation of ketone bodies (Ketogenesis) Location: hepatic mitochondria Material: acetyl CoA Rate-limiting enzyme: HMG-CoA synthase
Utilization of ketone bodies (ketolysis) at extrahepatic tissues Succinyl-CoA transsulfurase
HSCoA ATP AMP PPi Acetoacetate thiokinase - Lack of succinyl-CoA transsulfurase and Acetoacetate thiokinase in the liver.
Biological Significance • Ketone bodies replace glucose as the major source of energy for many tissues especially the brain, heart and muscles during times of prolonged starvation.
Normal physiological responses to carbohydrate shortages cause the liver to increase the production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation.