BC 368 Biochemistry of the Cell II Fatty

BC 368 Biochemistry of the Cell II Fatty Acid Catabolism, Chapter 17 April 21, 2015

Overview of Lipid Catabolism Triglycerides account for ~83% of our stored energy 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 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

Absorption of Dietary Fats Dietary lipids must be emulsified and packaged for transport in the bloodstream Bile salts are made from cholesterol in the liver; stored in gall bladder taurocholic acid

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 3: hydrolysis and entry into target tissues

Mobilization 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 Products

Back to the Matrix!

Activation of Fatty Acids by Co. A Fig 17 -5

Role of carnitine Fig 17 -6

Chemistry of Fat Catabolism 1904 classic experiment Fed to dogs 1875 -1946

Overview of β-Oxidation Fatty acids are broken down 2 -carbon units at a time, starting at the carboxyl end. Pieces are released as acetyl-Co. A. Fig 17 -7

Overview of oxidation

Reaction Steps Oxidation Hydration Oxidation Cleavage Fig 17 -8

Reaction 1: Oxidation Three isozymes of acyl-Co. A dehydrogase: Long chain (12 -18 C) Medium chain (4 -14 C) Short chain (4 -8 C) Fig 17 -8

Akee (Blighia sapida) “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

“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) FADH 2 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 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 Fats Both an isomerase and a reductase are necessary.

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

Essential fatty acid families ω-3 family ω-6 family H 3 C C 18: 2 ω-6 COOH Linoleic H 3 C C 18: 3 ω-3 • Corn Oil • Safflower Oil • Sunflower Oil H 3 C C 20: 4 ω-6 H 3 C COOH Arachidonic C 20: 5 ω-3 H 3 C C 22: 6 ω-3 COOH -Linolenic • Flaxseed Oil • Canola Oil • Soybean Oil COOH Eicosapentaenoic (EPA) COOH Docosahexaenoic (DHA) • Oily Fish • Fish Oil Capsules

A high fish diet correlates to lower acute MI (sudden heart attack) rates WEM Lands, Fish and Human Health, 1986

Historic incidence of heart disease in Oslo Acta Med Scand 1981; 210: 245 -8 Dietary Changes: Margarine, butter, CLO decreased from 159 to 79 g/d. Oily fish intake increased from 99 to 292 g/d.

Double-blind placebo-controlled study: giving DHA and EPA to people after a heart attack 100 g serving of farmed salmon = 2. 147 g DHA/EPA Marchioli R, et al. Circulation 2002; 105: 1897 -1903.

What do EPA and DHA do to lower the risk for heart disease? • Lower heart rate (Harris WS et al. Am J Cardiol 98: 1393 -1995, 2006) • Preventricular tachyarrhythmias (Billman GE et al. Proc Natl Acad Sci USA 1994; 91: 4427 -4430. ) • Lower blood pressure (Geleijnse et al. , J. Hypertens. , 2002; 20: 1493 -9) • Lower platelet function

Oxidation of Odd-Chain Fats Propionyl-Co. A is the last piece released. Propionyl-Co. A undergoes conversion to succinyl-Co. A, which enters TCA. Fig 17 -11

Vitamin B 12 Dorothy Crowfoot Hodgkin (1910 -1994) Box 17 -2

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 Chain Predominantly in the peroxisomes. Similar, but not identical, chemistry, using several auxiliary enzymes.

Very Long or Branched Chain Defects can lead to serious diseases such as Xlinked Adrenoleukodystrophy.

Control Fig 17 -13

Ketone bodies Made in the mitochondrial matrix of liver cells. Fig 17 -21

Ketone Bodies

Ketone Bodies Fig 17 -19

Ketone Bodies

Alcoholic Ketoacidosis “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 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.