BC 368

Biochemistry of the Cell II

Fatty Acid Catabolism, Chapter 17

April 21, 2015

Triglycerides account for ~83% of our stored energy

Overview of Lipid CatabolismOverview of Lipid Catabolism

Mobilized slower than carbs and only aerobically

Principal fuel for many organs (e.g., heart, liver)

More energy per gram than carbs (9 kcal vs. 4)

Transport of LipidsTransport of Lipids

Nonpolar lipids need to be escorted through the bloodstream via lipoprotein complexes.

Chylomicrons carry dietary lipids to tissues

VLDLs carry lipids synthesized in liver to tissues

LDLs carry cholesterol to tissues

HDLs carry cholesterol to liver from tissues

Dietary lipids must be emulsified and packaged for transport in the bloodstream

Absorption of Dietary FatsAbsorption of Dietary Fats

taurocholic acid Bile salts are made

from cholesterol in the liver; stored in gall bladder

Absorption of Dietary Fats

Step 1: emulsification by bile salts and hydrolysis by lipases

Absorption of Dietary Fats

Step 2: packaging for transport

Absorption of Dietary Fats

Step 2: packaging for transport

Absorption of Dietary Fats

Step 3: hydrolysis and entry into target tissues

Mobilization of Fat StoresMobilization of Fat Stores

Hormone (glucagon or epinephrine) binds to fat cell receptor, activating protein kinase A

Phosphorylation activates lipase and perilipin, triggering release of fatty acids

Fate of Triglyceride ProductsFate of Triglyceride Products

Fate of Triglyceride ProductsFate of Triglyceride Products

Back to the Matrix!Back to the Matrix!

Activation of Fatty Acids by CoAActivation of Fatty Acids by CoA

Fig 17-5

Activation of Fatty Acids by CoAActivation of Fatty Acids by CoA

Fig 17-5

Fig 17-6

Role of carnitine

Chemistry of Fat CatabolismChemistry of Fat Catabolism

Fed to dogs

1904 classic experiment

1875-1946

Overview of β-OxidationOverview of β-Oxidation

Fatty acids are broken down 2-carbon units at a time, starting at the carboxyl end.

Pieces are released as acetyl-CoA.

Fig 17-7

Overview of oxidation

Reaction StepsReaction Steps

Oxidation

Hydration

Oxidation

Cleavage

Fig 17-8

Reaction 1: OxidationReaction 1: Oxidation

Three isozymes of acyl-CoA dehydrogase:

Long chain (12-18C)Medium chain (4-14C)Short chain (4-8C)

Fig 17-8

“Pear-shaped fruit, with several moderate lobes and a red to yellow waxy skin. The skin, unripe fruit, and seeds are poisonous. The yellow, fleshy portion surrounding the aril is edible and has a nutty flavor.”

http://www.tradewindsfruit.com/akee.htm

Akee

(Blighia sapida)

“Down at the market you can hear Ladies cry out while on their heads they bear

Akee, rice, salt fish are nice,

And the rum is fine any time of year…”

Jamaica Farewell hypoglycin A

“Down at the market you can hear Ladies cry out while on their heads they bear

Akee, rice, salt fish are nice,

And the rum is fine any time of year…”

Jamaica Farewell hypoglycin A

Electron-Transfer Flavoprotein (ETF)

FADH2 reducing equivalents are passed to Electron- Transfer Flavoprotein (ETF), which leads to Q via an oxidoreductase

Fig 19-8

Reaction 2: hydration

Fig 17-8

Reaction 3: oxidation

Fig 17-8

Reaction 4: thiolytic cleavage

Fig 17-8

The synthetic compound shown here is a fat substitute.

a) What are the two molecular components of this compound and how does it compare to a triglyceride?

b) This compound is not digested. Why not?

c) Given the indigestibility of this compound, what is a potential problem for consumers?

d) This compound has been shown to deplete nutrients such as vitamin A and carotenoids. Why?

For more information, see www.american.edu/TED.olestra.htm

Oxidation of Unsaturated FatsOxidation of Unsaturated Fats

Double bonds are always cis.

An isomerase is needed to convert the cis double bond to the appropriate trans intermediate.

Fig 17-10

Polyunsaturated FatsPolyunsaturated Fats

Both an isomerase and a reductase are necessary.

Polyunsaturated FatsPolyunsaturated Fats

Some polyunsaturated fats are “essential” building blocks for signaling molecules such as the prostaglandins, thromboxanes, and leukotrienes.

COOH

C20:5 ω-3 Eicosapentaenoic(EPA)

H3C

Essential fatty acid familiesEssential fatty acid families

C18:3 ω-3

ω-3 family

-Linolenic• Flaxseed Oil• Canola Oil• Soybean Oil

C22:6 ω-3 Docosahexaenoic(DHA)

COOHH3C

• Oily Fish• Fish Oil Capsules

H3CCOOH

ω-6 family

C20:4 ω-6

C18:2 ω-6 Linoleic

Arachidonic

H3CCOOH

• Corn Oil• Safflower Oil• Sunflower Oil

H3C COOH

WEM Lands, Fish and Human Health, 1986

A high fish diet correlates to lower acute MI A high fish diet correlates to lower acute MI (sudden heart attack) rates(sudden heart attack) rates

Acta Med Scand 1981;210:245-8

Historic incidence of heart disease in OsloHistoric incidence of heart disease in Oslo

Dietary Changes:Dietary Changes: Margarine, butter, CLO decreased from 159 to 79 g/d. Oily Margarine, butter, CLO decreased from 159 to 79 g/d. Oily fish intake increased from 99 to 292 g/d. fish intake increased from 99 to 292 g/d.

Total Total mortalitymortalityreduced reduced by by 28%28%(p=0.027)(p=0.027)

Sudden Sudden deathdeathreduced reduced by by 47%47%(p=0.0136)(p=0.0136)

Marchioli R et al. Circulation 2002;105:1897-1903.

GISSIGISSI --Prevenzione:Prevenzione: Time Course of Clinical EventsTime Course of Clinical Events

>11,300 post>11,300 post--MI patients were given usual care with or MI patients were given usual care with or without without 850850 mg EPA+DHA (Omacor) for 3.5 yearsmg EPA+DHA (Omacor) for 3.5 years

Days

Pro

babili

ty

0 30 60 90 120 150 180 210 240 270 300 330 3600 30 60 90 120 150 180 210 240 270 300 330 360

Pro

babili

ty

0 30 60 90 120 150 180 210 240 270 300 330 3600 30 60 90 120 150 180 210 240 270 300 330 360

n-3 PUFAControl

n-3 PUFAControl

Days

0.59 (0.36– 0.97)p=0.037

0.72 (0.54– 0.96)p=0.027

0.47 (0.22– 0.99)p=0.048

0.53 (0.32– 0.88)p=0.0136

0.95

0.96

0.97

0.98

0.99

1.00

100 g serving of farmed salmon = 2.147 g DHA/EPA100 g serving of farmed salmon = 2.147 g DHA/EPA

Double-blind placebo-controlled study: giving Double-blind placebo-controlled study: giving DHA and EPA to people after a heart attackDHA and EPA to people after a heart attack

Marchioli R, et al. Marchioli R, et al. CirculationCirculation 2002;105:1897-1903. 2002;105:1897-1903.

What do EPA and DHA do to lower the risk for What do EPA and DHA do to lower the risk for heart disease?heart disease?

•Lower heart rate Lower heart rate (Harris WS et al. (Harris WS et al. Am J CardiolAm J Cardiol 98:1393-1995, 98:1393-1995, 20062006))

•Prevent ventricular tachyarrhythmias Prevent ventricular tachyarrhythmias (Billman GE et (Billman GE et al. al. Proc Natl Acad Proc Natl Acad Sci USA 1994;91:4427-4430.)Sci USA 1994;91:4427-4430.)

•Lower blood pressure Lower blood pressure (Geleijnse et al., J. Hypertens., 2002; (Geleijnse et al., J. Hypertens., 2002; 20:1493-9)20:1493-9)

•Lower platelet functionLower platelet function

Oxidation of Odd-Chain FatsOxidation of Odd-Chain Fats

Propionyl-CoA is the last piece released.

Propionyl-CoA undergoes conversion to succinyl-CoA, which enters TCA.

Fig 17-11

Vitamin B12

Box 17-2

Dorothy Crowfoot Hodgkin (1910-1994)

Vitamin B12

Box 17-2

Dorothy Crowfoot Hodgkin (1910-1994)

Nobel prize winners of 1964 (from left to right): C.H. Tauns, A.M. Prokhorov, N.G. Basov (all in physics), D. Crowfoot-Hodgkin, K.E. Bloch, and F. Lynen

Very Long or Branched ChainVery Long or Branched Chain

Predominantly in the peroxisomes.

Similar, but not identical, chemistry, using several auxiliary enzymes.

Very Long or Branched ChainVery Long or Branched Chain

Defects can lead to serious diseases such as X-linked Adrenoleukodystrophy.

Control

Fig 17-13

Ketone bodies

Fig 17-21

Made in the mitochondrial matrix of liver cells.

Ketone Bodies Ketone Bodies

Ketone Bodies Ketone Bodies

Fig 17-19

Ketone Bodies Ketone Bodies

“Forensic pathologists are familiar with alcohol abusers, who are found dead and in whom the cause of death cannot be ascertained. In order to examine the possible role of ketoacidosis for the cause of death in this group of alcohol abusers, the concentrations of ketone bodies were determined in post-mortem blood specimens…”

Thomsen JL, Felby S, Theilade P, Nielsen E. (1995) Alcoholic ketoacidosis as a cause of death in forensic cases. Forensic Sci Int. 75, 163-71.

Alcoholic Ketoacidosis Alcoholic Ketoacidosis

Thomsen JL, Felby S, Theilade P, Nielsen E. (1995) Alcoholic ketoacidosis as a cause of death in forensic cases. Forensic Sci Int. 75, 163-71.

Alcoholic Ketoacidosis Alcoholic Ketoacidosis