(L18) Oxidation of Fatty Acids: Ketogenesis

Lipids

heterogenous group of compounds (fats, oils, steroids, waxes)

Fats

stored in human body in various forms (major storage form is triglycerides)

Oils

fats in liquid states

steroids

large class of organic compounds with characteristic molecular structure with cyclic nucleus resembling phenanthrene (A,B,C) to which a cyclopentane (D) is attached

waxes

esters of fatty acids with high molecular weight alcohols

triglycerides

glycerol and 3 fatty acids
- impermeable from adipose tissue

fatty acid

long hydrocarbon chains with carboxylic acid at end
- high energy value (ATP)
- broken down through B-oxidation

palmitic acid

saturated fatty acid

oleic acid

monounsaturated fatty acid

linoleic acid

polyunsaturated fatty acid

B-oxidation overview

1. transport from adipose tissue to target cells
2. entry into cytoplasm and mitochondria
3. oxidative catabolism inside mitochondrial matrix

lipase

breaks down triglycerides to glycerol and "free" fatty acids
- never "free"; in plasma attached to albumin and in cells attached to fatty acid binding protein
- hormone sensitive hence referred to as HSL

regulation of lipase

- activated by glucagon, ACTH, epinephrine, and vasopressin
- inhibited by insulin and prostaglandin E

transport from adipose tissue to targets

1. lipase breaks down triglycerides
2. free fatty acids are permeable
3. transported to target cells via blood
4. entry into cytoplasm and mitochondria
5. FFA enter cells through fatty acid transporter
6. short chain and medium chain FFA diffuse freely into mitochondria but long chain (more than 12 C) must be activated

fatty acids must first be converted to

Acyl-CoA
(generalized term; palmitic acid --> palmitoyl-CoA_
- conversion catalyzed bu Acyl-CoA synthetase
- uses ATP

carnitine shuttle

shuttles long-chain fatty acids into mitochondrial matrix for B-oxidation
1. fatty acids converted to Acyl-CoA via Acyl-CoA synthetase
2. acyl groups are transferred from CoA to carnitine by CAT I (carnitine acyl transferase I)
3. acylcarnitine formed can be carried into matrix by carnitine acylcarnitine translocase
4. acyl group transferred back to CoA by CAT II (carnitine acyl transferase), reforming acyl-CoA, carnitine released is transported back into intermembrane space

3 important enzymes for carnitine shuttle

- Carnitine acyl transferase I (CAT I) RATE LIMITING
- Carnitine acylcarnitine translocase
- Carnitine acyl transferase II (CAT II)

B-oxidation

1. fatty acid oxidase (several enzymes in matrix or inner membrane) catalyze oxidation of acyl-CoA to acetyl-CoA
2. large quantities of FADH2 and NADH generated and used to form ATP by oxidative phosphorylation
3. breaked down of palmitic acid = 8 acetyl-CoA, 7 NADH, 7 FADH2

B-oxidation pathway

1. removal of 2 H+ from a and B-carbon atoms (catalyzed by Acyl-CoA dehydrogenase and requires FAD); creates double bond; rare trans bond in natural fatty acids

2. water is added to saturated double blood and for 3-L-hydroxyacyl-CoA (catalyzed by enoyl-CoA hydratase)

3. 3-L-hydroxyacyl-CoA undergoes dehydrogenation to form B-ketoacyl-CoA (NAD+ coenzyme involved)

4. B-ketoacyl-CoA is split at 2,3 position forming acetyl-CoA and new acyl-CoA two carbons shorter than original

5. shorter acyl-CoA reenters oxidative pathway

oxidation of fatty acids produces

1 FADH2, 1 NADH (one cycle)
- ox of C16 fatty acid generates 106 ATP

modified form of B-oxidation in peroxisomes

leads to breakdown of very long-chain fatty acids with formation of acetyl-CoA and H2O2 (H2O2 is broken down by catalase)

fatty acids with odd number of carbon atoms

oxidized by pathway of B-oxidation producing acetyl-CoA until 3-carbon (propionyl-CoA) residue remains

Propionyl-CoA

converted to succinyl-CoA
- propionyl-CoA = only part of fatty acid that is glucogenic

ketone body synthesis

ketogenesis
- alternative source of energy if carbs are low (starvation)
- may occur if TCA cycle is unable to function (DKA; alcoholism)
- produced in mitochondria of liver from acetyl-CoA (extrahepatic tissues)

3 ketone body types

acetoacetate
B-3-hydroxybutyrate/D-3-hydroxybutyrate
acetone

ketone body pathway

- 2 acetyl-CoA condensed to form acetoacetyl-CoA (catalyzed by thiolase)
- HMG-CoA synthase uses water to add another molecule of acetyl-CoA to B-carbon of acetoacetyl-CoA to form B-hydroxy-B-methylglutaryl-CoA (HMG-CoA)
- branched 6 carbon compound and intermediate in
synthesis of cholesterol in cytosol
- 1 acetyl-CoA is cleaved from HMG-CoA by HMG-CoA lyase producing acetoacetate (1st ketone body formed, acetyl-coA formed is recycled)
- acetoacetate can either be reduced to D-B-hydroxybutyrate by DBHB dehydrogenase in NADH + (H+) dependent reaction or undergo spontaneous decarboxylation to form acetone
- 1 mol of acetoacetate or 3-hydrobutyrate yields 19 or 21.5 mol of ATP, respectively

rate limiting enzyme of ketogenesis

HMG-CoA synthase

Conditions ketogenesis is used

1. starvation - gluconeogenesis induced depletion of oxaloacetate
2. alcoholism - alcohol induced change in NADH to NAD+ ratio (increased NADH, no TCA); hypoglycemia
3. Diabetic ketoacidosis (DKA) - period of starvtion for type 1 diabetics (depletion of oxaloacetate); hyperglycemia due to repeated gluconeogenesis

Impairment of fatty acid oxidation

- malonyl CoA inhibits CAT 1
- systemic primary carnitine deficiency (no transport of Acyl-CoA into mitochondrial membrane)
- hypoketotic
- hypoglycemia
- myopathic CAT II deficiency
-myoglobinuria
- hypotonia and weak muscles
- increased triglycerides in muscles

number of acyl-CoA dehydrogenase types in mitochondria

4

Medium-chain fatty acyl CoA dehydrogenase (MCAD) deficiency

- autosomal recessive disorder
- most common inborn errors of metabolism and error of fatty acid oxidation
- high incidence in caucasians of Northern European descent
- avoid fasting
- sudden infant death syndrome or Reye syndrome

MCAD results

- decreased ability to oxidize fatty acids with 6-10 carbons (accumulate and measure in urine)
- severe hypoglycemia (tissues increase reliance on glucose)
- hypoketonemia (decreased production of acetyl-CoA)