Lipid Catabolism

Lipolysis (Hydrolyzation of fat)

There are 3 steps

1.    Activation of Hormone Sensitive Lipase (HSL)

2.    Fate of Glycerol

3.    Fate of fatty acids

 

1.    Activation of Hormone Sensitive Lipase (HSL)

 

·       Done by hormone sensitive lipase active form (phosphorylated form)

·       HSL           🠚                      HSL (active)-PO₄
                 Protein Kinase

1.                                

1.    Fate of glycerol

 

·       In adipocytes glycerol cannot be metabolized, because of lack of glycerol kinase

·       Glycerol transported to liver via blood

·       In liver, it gets phosphorylated

o   Phosphorylated glycerol use to synthesized of triacyl glycerol via blood

o   Converted to DHAP in gluconeogenesis/glycolysis

 

2.    Fate of fatty acids

·       Free (unesterified) fatty acids move through cell membrane of adipocytes, bind to Albumin

·       Transported to tissues and enter into cells for oxidation and release energy

 

Fatty acid oxidation (Beta oxidation of fatty acids)

·       Catabolism of saturated fatty acids

·       End product – acetyl CoA (2C)

 

Steps

1.    Activation of fatty acids

2.    Penetration of fatty acyl CoA through mitochondrial membrane

3.    Beta oxidation of fatty acid

 

1.    Activation of fatty acids

 

Fatty acids must be activated in the cytoplasm before being oxidized in the mitochondria matrix

Fatty acid                        Fatty acyl CoA (active) + 2PPi + AMP

                        Fatty acyl CoA synthase

                        ( thiokinase)

 Transport of fatty acil CoA into mitochondria

·       Inner mitochondrial membrane impermeable to CoA

·       Therefore, need a specialized carrier – Carnitine

·       Known as Carnitine shuttle -rate limiting step

 

 

2.    Penetration of fatty acyl CoA into mitochondria

 

·       Only long chain fatty acids need Carnitine

·       Short term fatty acids directly enter to the mitochondria matrix

·       Carnitine is made up of Lys and Met AA

·       Acyl group transfer from CoA to Carnitine by CPT – I (forms acyl carnitine)

·       Acyl carnitine transported into the mitochondria matrix by translocase (exchange carnitine)

·       Inner mitochondrial membrane – transfer acyl group from carnitine to CoA (reforms acyl CoA and liberates C) – CPT II

 

CPT – Carnitine Palmitoyl Transferase

            

1.    Beta oxidation of fatty acid

·       Process of fatty acid oxidation in known as beta oxidation

·       Sequential removal of 2 carbon units

·       Fatty acid chain shortens at beta C

·       Consists of four reactions

·       Each round of beta oxidation produces

-        one mole of NADH

-        one mole of FADH2

-        one mole of acetyl CoA (enters the TCA cycle)

 

·       Further acetyl CoA is oxidized via TCA cycle to CO2 with concomitant generation of  

-        3 moles of NADH

-        1 mole of FADH2

-        1 mole of ATP

·       These enters respiratory pathways for the production of ATP

·       The oxidation of fatty acids yields significantly more energy per C atom than does the oxidation of carbohydrates

Example

Palmitoyl CoA – 16 Carbons

7 cycles happen

            7NADH * 3ATP                    = 21ATP

            7FADH2 * 2ATP                   = 14ATP

            8AcetylCoA * 12 ATP         = 96ATP

            Total                                       = 131ATP

 

2 moles of ATP used during the activation of fatty acid

                        131 ATP – 2 ATP = 129ATP

 

Alternative Oxidation Pathways

1.    Odd number of fatty acid chains

·       Complete beta oxidation yield acetyl CoA unit + a single mole of Propionyl CoA

·       Propionyl CoA converted in an ATP dependent three step pathway to Succinyl CoA

·       The Succinyl CoA enters the TCA cycle for further oxidation

 

2.    Oxidation of unsaturated fatty acids

·       It is essential as the same process of saturated fatty acids

·       PUFA and MUFA need 2 additional enzymes

§  Enoyl CoA isomerase

§  Dienoyl CoA reductase

 

Clinical significance of fatty acid metabolism

 

·       Mainly involved in oxidation process

·       Disorders fall into 4 main groups

1.    Carnitine deficiency

·       Causes ability to transport long chain fatty acid into the mitochondria (inner membrane is impermeable to long chain fatty acids)

·       Occurs in protein deficiencies

2.Carnitine Palmitoyl deficiency

·       CPT I deficiency

·       CPT II deficiency

2.    Deficiencies in Acyl- CoA dehydrogenases

3.    Refsum disease

 

Regulation of fatty acid metabolism

 

·       Fed state – insulin increased

·       Starvation – decreased insulin – lipogenesis decreased, catabolism increased

 

Two mechanisms

1.    Short term regulation

Mediated through events such as substrate availability, allosteric effects and or enzyme covalent modifications

2.    Long term regulation

Is achieved by alteration of the rate of enzyme synthesis and turn over