Download Chapter 19 Lipid Metabolism

Chapter 19 Lipid Metabolism
Properties:
1) hydrophobic
2) Can be stored without water in adipose tissue (specialized connective tissue)
3) The storage form is triacylglyceride (TAG). TAGs yield 2½ times more ATP than glycogen by weight
4) Average 70 kg person stores about 350 g of liver and muscle glycogen (1400 Cal), but store enough TAG to
survive without food for several weeks.
Sources of Fatty Acids:
1) Diet
An adult man ingest 50 -150 g of lipid/day. TAG make up 90% of dietary fats.
Ingest TAG → converted to fatty acids and solubilized by bile acids → absorbed through the epithelial
cells of the intestines → converted back to TAG → carried by chylomicrons to the lymph system then into the
bloodstream.
→Must have a high proportion of unsaturated fatty acids in the diet because humans are unable to synthesize
fatty acids with double bonds near the methyl end of the molecule.
2) Biosynthesis
Can synthesize fatty acids from sugars, some amino acids, and other fatty acids.
→Fatty acids are synthesized from acetyl-CoA in the cytosol. The body synthesizes palmitic acid (16:0), and
then modifies it to form other fatty acids.
Synthesis of Palmitic Acid
8 acetyl-CoA + 7 ATP +14NADPH +14H+ → palmitic acid +14NADP + + 8CoA + 7ADP + 7Pi + 6H2 O
E= fatty acid synthase-composed of all the enzymatic units necessary for FA synthesis
Features of fatty acid synthesis:
1) Fatty acids are made from the addition of C2 units derived from acetyl-CoA
2) The acetate units are activated by the formation of malonyl-CoA
3) The addition of the C2 units to the growing chain is driven by decarboxylation of malonyl-CoA
4) The elongation continues until the growing chain reaches 16 carbons in length
5) Other enzymes may then add double bonds, more carbons, or hydroxyl groups.
Step 1: acetyl-CoA + HCO3 - + ATP → malonyl-CoA + H2 O +ADP + Pi E=acetyl-CoA carboxylase
This step commits the acetate group to fatty acid synthesis. The enzyme is product (palmitate) inhibited
and activated by citrate (allosteric).
The subsequent decarboxylation of malonyl-CoA drives the otherwise thermodynamically unfavorable
condensation reaction.
Rest: The rest of the steps catalyzed by fatty acid synthase. Each malonyl-CoA transfers to CH2 groups to the
growing chain.
→There are three principal sources of acetyl-CoA:
1) amino acid degradation produces cytosolic acetyl-CoA (insufficient)
2) fatty acid oxidation produces mitochondrial acetyl-CoA
3) glycolysis yields cytosolic pyruvate which is transported into the mitochondria to produce acetyl-CoA
So must transfer acetyl-CoA from the mitochondria using the citrate shuttle system (in chapter 16 notes).
Regulation:
Tightly regulated through hormones and diet. The net effect of the hormones is to phosphorylate
(dephosphorylate) acetyl-CoA carboxylase. Diet: high carbohydrate diet-activates, fat free diet-activates, high
fat diet- inhibits, fasting- inhibits.
Synthesis of Other Fatty Acids
1) elongation- occurs in ER and mito- a thiolase enzyme is used to transfer an acetyl-CoA to the chain.
2) desaturation-carried out in eukaryotes by desaturase enzymes:
R-CH2 -CH2 -(CH2 )7 -COO- +NADPH + H+ +O2 → R-CH=CH-(CH2 )7-COO- + NADP + + 2H2 O
R must contain at least 6 carbons.
3) hydroxylation- produce a hydroxyl fatty acids
Formation of TAG
Most tissues convert fatty acids to TAG, but mostly in the liver and adipose tissue.
1) form an activated fatty acid:
RCOO- + ATP + CoA → RCO-SCoA +AMP + PPi (eq to 2ATP)
E= acyl-CoA synthetase
2) Attach activated fatty acid to GAP or DHAP
Storage of TAG
Can store in the short term in about all cells as liquid droplets in the cytoplasm. Store long term in adipose
tissue.
Hormones (adrenaline, glucagons, ACTH) signal the release of fatty acids from adipose tissue.
Adipose cell
TAG
? lipases→under hormonal control
Fatty acids
enters
bloodstream
attached to carrier
Carriers:
1) Serum albumin
2) Lipoproteins
chylomicrons
from intestines
HDL, LDL, VLDL
3) Ketone bodies
Fatty Acids as Energy Source
Utilization varies from tissue to tissue and depends on metabolic state of the body (fed, fasted, exercise,
at rest).
→nervous tissue uses little to none
→cardiac and skeletal- major energy source
Sequentially remove 2-carbon fragment (acetyl-CoA) after steps of dehydrogenation, hydration, and oxidation.
Step 1: Activate the fatty acid in the ER by attaching CoA:
RCOO- + ATP + CoA → RCOSCoA + AMP + PPi +H2 O
E= acyl-CoA transferase
(eq to 2ATP)
→ Carnitine is then used to shuttle the acyl group across the inner mitochondrial membrane into the
mito. matrix for subsequent β-oxidation.
Step 2: β-oxidation
Each round of β-oxidation produces one mole of NADH, one mole of FADH2 and one mole of
acetyl-CoA. The acetyl-CoA--- the end product of each round of β-oxidation--- then enters the TCA
cycle, where it is further oxidized to CO2 with the concomitant generation of three moles of NADH, one
mole of FADH2 and one mole of ATP. The NADH and FADH2 generated during the fat oxidation and
acetyl-CoA oxidation in the TCA cycle then can enter the respiratory pathway for the production of
ATP.
1) Form a trans double bond at C3 by the enzyme acyl-CoA dehydrogenase. Oxidation of acyl-CoA
results in the reduction of FAD to FADH2 .
2) Hydration of the double bond by enoyl-CoA hydrates (OH on C3).
3) Oxidize the OH group with hydoxyacyl-CoA degydrogenase. Reduce NAD+ to NADH.
4) Cleavage of the 2 carbon fragment by a thiolase to form acetyl-CoA and fatty acyl-CoA (-2 carbons).
ATP Formation:
1) Palmitic acid 16:0
Undergoes 7 cleavages (7 rounds of β oxidation) forming 8 acetyl-CoA
→8 acetyl-CoA x 12 ATP
= 96 ATP
→7 cycles of β-oxidation x 5 ATP = 35 ATP
→activation of fatty acid
=-2 ATP
Total
129 ATP
Remember: Fatty acid synthesis occurs in the cytosol and uses NADPH and β-oxidation occurs in the
mitochondria and uses FAD and NAD+.
2) Odd number fatty acid: (rare in mammals)
Go through β-oxidation, in last cycle produce 1 acetyl-CoA and 1 propionyl-CoA. The propionyl is then
converted to succinyl-CoA (TCA intermediate) or used in glucose synthesis. When determining ATP, we will
ignore the propionyl-CoA.
Fatty acid 23:0
1 propionyl-CoA (ignore)
10 acetyl-CoA x 12 ATP
=120 ATP
10 cycles of β-oxidation x 5 ATP
= 50 ATP
activation
=-2 ATP
TOTAL
168 ATP
3) Unsaturated fatty acids:
The cis double bond must be converted to trans by enoyl-CoA isomerase. This replaces the first step of
β-oxidation (only the cycle with the double bond), thus no FADH2 is produced during this cycle (-2 ATP).
Fatty acid 18:1
9 acetyl-CoA x 12 ATP
= 108 ATP
8 cycles of β-ox. x 5ATP
= 40 ATP
activation
= -2 ATP
double bond
= -2 ATP
TOTAL
144 ATP
β-oxidation in the peroxisomes
Also a 4 enzyme cycle to break off an acetyl-CoA from a fatty
acid. There are 2 major differences from β-oxidation in the
mitochondria.
1) Works best on very long chain fatty acids. Functions to shorten fatty
acids then sends them to the mitochondria to complete oxidation.
2) The first step involves acyl-CoA oxidase which catalyzes the
formation of the double bond. The electrons are shuttled through
FADH2 to O2 producing H2 O2 . Therefore, β-oxidation in the
peroxisomes produces only an NADH molecule that can be sent to
electron-transport (3 ATP/cycle)
Ketone Bodies:
Formed primarily within the mitochondria of the liver. Ketone bodies serve as fuel for cardiac and skeletal
muscle during starvation and insulin deficiency. They are a source of fuel for the brain when glucose is in short
supply. They are used by the central nervous system during starvation. Acetoacetate is produced from the
condensation of 2 acetyl-CoA through three different enzymes.
→Acetoacetate can undergo spontaneous decarboxylation to produce acetone:
(ketone body)
(ketone body)
→acetoacetate can also be converted to another ketone body, β-hydoxybutyrate:
The extent of this reaction depends on the pool of NADH in the body.
→When the ketone bodies are used for fuel, they are converted back to acetyl-CoA which enters the TCA cycle.
→ Diabetics produce acetoacetate faster than can be metabolized, so their breath will smell like acetone.
→ A high amount of ketone bodies in the blood can lead to ketosis (acidosis) over time.
Cholesterol Metabolism
Uses:
1) in cell membranes
2) precursor for steroids and bile acids
Biosynthesis:
Formed from acetate units (primarily in the liver). The enzyme HMG-CoA reductase is the principal
site of regulation in cholesterol synthesis. The body regulates this enzyme in three ways:1) covalent
modification, (2) degradation, and (3) gene expression. This enzyme is also inhibited by the fungal product
compactin, and the drugs lovastatin, simvastatin (Zocor), pravastatin (pravochol).
In liver- convert to bile acids or esterified by ACAT (acyl-CoA cholesterol acyltransferase). Cholesterol esters
are carried in the bloodstream in lipoprotein complexes (HDL, LDL, etc.).