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Click to edit Master title style • Edit Master text styles • Second level

Click to edit Master title style • Edit Master text styles • Second level Lipid-L 4 • Third level • Fourth level • Fifth level Lipid Metabolism 1

Fatty Acid Oxidation Click to edit Master title style • Edit Master text styles

Fatty Acid Oxidation Click to edit Master title style • Edit Master text styles • Second level • Third level • Fourth level • Fifth level Prof. Dr. Randa Ali-Labib Prof. Dr. Hanan Shehata Medical Biochemistry and Molecular Biology Department 2

Intended Learning Outcomes Click to edit Master title style By the end of this

Intended Learning Outcomes Click to edit Master title style By the end of this lecture, the student should be able to: • Edit Master text styles • Second level 1. Elaborate on the Entry of short, medium and long chain • Third level fatty acids • Fourth intolevelthe mitochondria. • Fifth level 2. Summarize and /or illustrate steps of the translocation of long chain fatty acids into mitochondria. 3. List the sources and inhibitors of carnitine transport. 4. Relate some clinical changes and /or abnormalities that can be associated with carnitine deficiencies and other metabolic changes in lipolysis or fatty acid oxidation processes. ©

Click to edit Master title style • 5. Edit. Summarize Master text styles the

Click to edit Master title style • 5. Edit. Summarize Master text styles the reactions of beta-oxidation of • fatty Second acids. level • Third level 6. Calculate the • Fourth level energy yield of even no. fatty acid oxidation. • Fifth level 7. Describe the oxidation of odd number fatty acid. 8. Describe the oxidation of unsaturated fatty acid. 9. State the regulation of fatty acid oxidation. 10. Differentiate between the different types of fatty acid oxidation. 11. Compare between FA synthesis and oxidation.

Adipose Tissue and Energy Storage Click to edit Master title style White adipose tissue

Adipose Tissue and Energy Storage Click to edit Master title style White adipose tissue • mainly concerned with energy storage as TAG forms Edit Master text styles the • major component (80%) of it. • Second level • Made of • spherical cells, with very few mitochondria. Third level • Fourth level • Fifth level Brown adipose tissue • involved in thermogenesis. • made of polygonal cells, with numerous mitochondria (give it brown color) and numerous cytochromes as well. • It is primarily important in newborns and some hibernating animals. It is also, reduced or absent in obese persons.

Brown Adipose Tissue involvement in thermogensis: Click to edit Master title style Characteristics of

Brown Adipose Tissue involvement in thermogensis: Click to edit Master title style Characteristics of brown tissue: • Edit Master text styles - blood + mitochondria& cytochromes • Secondsupply level • Third level - Low activity • Fourthof level ATP synthase • Fifth level -Uncoupling of mt oxidative phosphorylation due to: thermogenin protein which dissipates the electrochemical potential across the mt membrane. So, oxidation produce much heat and little free energy is trapped in ATP.

Mobilization of stored fat (lipolysis) Click to edit Master title style Mobilization of Stored

Mobilization of stored fat (lipolysis) Click to edit Master title style Mobilization of Stored Fats (lipolysis) • Edit Master text styles ready • Second forlevel. Oxidation of Fatty Acids • Third level TAGs provide concentrated stores of metabolic energy because they are highly reduced and largely anhydrous. The yield from complete oxidation of fatty acids to CO 2 and H 2 O is nine kcal/g fat (as compared to four kcal/g protein or carbohydrate, • Fourth level • Fifth level

Fatty Acid Oxidation Click to edit Master title style v 1 -( )Beta-oxidation of

Fatty Acid Oxidation Click to edit Master title style v 1 -( )Beta-oxidation of FA (Major catabolic pathway) Ø Activation of FA • Edit Master text styles Ø Transport of LCFA into mitochondria: • Second level (Carnitine shuttle-carnitine sources-carnitine deficiency) • Third level Fourth level Ø Entery of • short and medium chain FA? • Fifth level Ø Steps of oxidation Ø Energetics of oxidation Ø Oxidation of odd-number FA Ø Oxidation of unsaturated FA Ø -oxidation in peroxisome for very long chain FA. v 2 -Aternative ways of oxidation Ø( )Alpha-oxidation of FA Ø( )Omega-oxidation of FA

Click to edit Master title style • Edit Master text styles • Second level

Click to edit Master title style • Edit Master text styles • Second level • Third level • Fourth level • Fifth level Matrix

Activation of LCFA in the cytoplasm utilizing ATPClick occurs: to edit Master title style

Activation of LCFA in the cytoplasm utilizing ATPClick occurs: to edit Master title style • Edit Master text styles • Second level • Third level • Fourth level • Fifth level First Step +PPi

The FA Click to edit activated Master title style needs to go to •

The FA Click to edit activated Master title style needs to go to • Edit Master text styles the mitochondrial matrix • Second level How? • Third level • Fourth level • Fifth level Transport of acyl Co. A into mitochondria: (Carnitine shuttle) Carnitine shuttle to allow LCFA to enter the matrix (as inner mitochondrial membranes are impermeable to Co. A).

Click to edit Master title style • Edit Master text styles • Second level

Click to edit Master title style • Edit Master text styles • Second level • Third level • Fourth level • Fifth level LCFA transport (Carnitine Shuttle): 1 - Acyl group transferred from Co. A to carnitine by carnitine palmitoyltransferase. I(CPT-I) or CAT-I for carnitine acyltransferase I. 2 -acylcarnitine enters the matrix in exchange for free carnitine by carnitine–acylcarnitine translocase. 3 -(CPT-II, or CAT-II) catalyzes the transfer of the acyl group from carnitine to Co. A in the matrix; regenerating free carnitine.

Of Carnitine Click to edit Master title style 1 diet ( meat products). •

Of Carnitine Click to edit Master title style 1 diet ( meat products). • Edit Master text styles Second level 2 - • Endogenous synthesized carnitine (lysine • Third level and methionine) by liver & kidney but not in • Fourth level • Fifth level skeletal or heart ms. Although skeletal ms has 97% of all carnitine in the body, they are dependent on carnitine provided by blood from endogenous synthesis or diet.

Inhibitor of the carnitine Shuttle: Click to edit Master title style • Malonyl Co.

Inhibitor of the carnitine Shuttle: Click to edit Master title style • Malonyl Co. A inhibits CAT-I preventing the of styles long-chain acyl groups into the • Editentry Master text • Second level mitochondrial matrix. • Third level • Fourth level • Fifth level • Turning on the fatty acid synthesis pathway turns off the -oxidation pathway.

Click to edit Master title style • Edit Master text styles • Second level

Click to edit Master title style • Edit Master text styles • Second level • Third level • Fourth level • Fifth level -FAs < 12 C (e. g milk) passes without the aid of the shuttle. They are activated to their Co. A derivatives by matrix enzymes for oxidation. So, oxidation is not dependent on carnitin shuttle, and it is not subject to inhibition by malonyl Co. A

Carnitine Click to edit. Deficiency Master title style • Edit Masterin textastyles Results decreased

Carnitine Click to edit. Deficiency Master title style • Edit Masterin textastyles Results decreased ability of tissues • Second level to • use Third level. LCFA as a metabolic fuel. • Fourth level • Fifth level

1 ry Carnitine deficiency: =Congenital in any of CPT system. Click to edit deficiencies

1 ry Carnitine deficiency: =Congenital in any of CPT system. Click to edit deficiencies Master title style • Edit Master text styles ( liver) • Second level (cardiac & skeletal ms) • Third level • Fourth level • Fifth level Inability to use LCFA for fuel → ATP impairs the ability to synthesize Glucose in fast (Gluconeogenesis). This leads to: severe Hypoglycemia. Cardiomyopathy to muscle weakness

y r e Click to edit Master 2 title istyle n t y i

y r e Click to edit Master 2 title istyle n t y i c n r ien a c i • Edit Master text styles c f e • Second level d • Third level • Fourth level • Fifth level (de . ) s e t in n t e i i at carn Maln P e utrit f s o a ion p ise esis atien d ( vege h r t ts e taria n v i y L ds n) e s a cre Increased requirement for carnitine ( pregnancy, severe infections, or trauma. )

After Transport into Mitochondrial Matrix Click to edit Master title style • Edit Master

After Transport into Mitochondrial Matrix Click to edit Master title style • Edit Master text styles Carnitine long • Secondcarries level • Third level chain activated fatty • Fourth level acids into • Fifth the mitochondrial Matrix. Fatty acid is ready now for oxidation lets start 19 CAT II

Steps of β-oxidation: (4 Click steps ): to edit Master title style Oxidation (FADH

Steps of β-oxidation: (4 Click steps ): to edit Master title style Oxidation (FADH 2) • Edit Master text styles • Second level • Third level • Fourth level Hydration (add H 2 O) • Fifth level Oxidation (NADH) Thiolytic cleavage to releases acetyl Co. A.

For even saturated FAs to edit title No. Click of Acetyl Co. AMaster produced=

For even saturated FAs to edit title No. Click of Acetyl Co. AMaster produced= (number of carbons/2) style Oxidation • Edit Master text styles NO. of • cycles= Second level Third level (number of • carbons/2) – 1 • Fourth level • Fifth level Each cycle → 1(acetyl Co. A +NADH+ FADH 2). except the final thiolytic cleavage produces 2 acetyl Co. A [NB: Acetyl Co. A is a positive allosteric effector of pyruvate carboxylase thus linking FA oxidation and gluconeogenesis. ] Hydration Oxidation Thiolase

The energy yield is Click to edit Master title style high. For example, the

The energy yield is Click to edit Master title style high. For example, the oxidation of palmitoyl Co. A (16 C. ) to CO 2 and H 2 O produces • Edit Master text styles Second level • 16/2= 8 • Aceyl Co. A – 1= 7 Cycles. 7 NADH , 7 FADH 2. • Third level • Fourth level • Fifth level • So, 7× 5= 35 ATP. 5 ATP/cycle • 8 Acetyl Co. A × 12 (TCA) = 96+35=131 ATP- 2 (of activation)= 16/2 -1=7 cycle = (7 X 2)+(7 x 3)+(8 x 12) =131 131 -2=129 ATP 1 NADH → 3 ATP • 1 FADH 2 → 2 ATP • 129 ATP.

Special Cases Click to edit Master title style • Edit Master text styles •

Special Cases Click to edit Master title style • Edit Master text styles • Second level • Third level Oxidation of odd number fatty • Fourth level acids • Fifth level The β-oxidation of a saturated odd FA proceeds the same as even until the final three carbons propionyl Co. A is reached. Propionyl Co. A is metabolized to succinyl Co. A, Which can enter TCA.

Click to edit Master title style • Edit Master text styles • Second level

Click to edit Master title style • Edit Master text styles • Second level Propionyl Co. A finds its way Fourth level to the TCA either via the • Fifth level formation of succinyl Co. A or via the conversion to glucose by the process of gluconeogenesis. • Third level •

Special Cases Click to edit Master title style Oxidation fatty acids: • Edit Masterof

Special Cases Click to edit Master title style Oxidation fatty acids: • Edit Masterof textunsaturated styles • Second level of unsaturated FA provides less The oxidation • Third level energy than • saturated FA because unsaturated FA Fourth level • Fifth level are less reduced and, therefore, fewer reducing equivalents can be produced from unsaturated f. A. Energy yield is less than that of the oxidation saturated FA by 2 ATP less for each double bond. (i. e. less production of reducing equivalent as the first step of beta oxidation is skipped)

Regulation ofstyle β Oxidation Click to edit Master title • Edit Master text styles

Regulation ofstyle β Oxidation Click to edit Master title • Edit Master text styles • Second level • Third level • Fourth level • Fifth level

Click to edit Master title style • Hormonal Regulation Edit Master text styles (availability

Click to edit Master title style • Hormonal Regulation Edit Master text styles (availability of free fatty acids) • Second level • Third level • Fourth level • Fifth level Carbohydrate feeding release of insulin. Insulin lipogenesis and available for oxidation. lipolysis FFA Anti-insulin hormones produce the reverse thus increasing FFA available for oxidation.

Remember : In mitochondria there are different types of fatty acyl Co. A dehydrogenases

Remember : In mitochondria there are different types of fatty acyl Co. A dehydrogenases which are specific for short, medium, long • Edit Master text stylesfatty acids. https: //youtu. be/j 90 j. GPn 3 FGY Click to edit Master title style • Second level Medium chain fatty acyl Co. A • Third level • Fourth level dehydrogenase deficiency(MCAD) • Fifth level • An autosomal recessive disorder • There is defect in oxidation of middle chain fatty acids. • Because, there is reliance on glucose so hypoglycemia on fasting should be avoided in these patients. • MCAD has been originally reported to be a cause of some cases as sudden infant death syndrome (SIDS) or Reye syndrome.

Click to edit Master title style β-Oxidation • Edit Master text styles in the

Click to edit Master title style β-Oxidation • Edit Master text styles in the peroxisome • Second level • Third level • Fourth level β-Oxidation in the peroxisome is a • Fifth level preliminary step For shortening VLCFA, 22 C, up to 8 C. The Shortened FA is transferred to mitochondria for further beta oxidation in mitochondria.

Peroxisome in contrast to mitochondrial βoxidation: Click to edit Master title style * Initial

Peroxisome in contrast to mitochondrial βoxidation: Click to edit Master title style * Initial • Edit Master text styles dehydrogenation in • Second level peroxisomes is an • Third level FAD-containing • Fourth level • Fifth level acyl Co. A oxidase. (Here FADH 2 produced is oxidized by molecular oxygen to H 2 O 2 which is reduced to water by catalase and no ATP is produced by this step)

Click to edit Master title style Zellweger syndrome • Edit. It Master styles is

Click to edit Master title style Zellweger syndrome • Edit. It Master styles is text a genetic defect in the • Second level • Third level β-Oxidation in the peroxisome • Fourth level that leads • Fifth levelto accumulation of VLCFA and production of neurological symptoms. https: //youtu. be/8 Zd. RKd 8 jv 5 M

Click to edit Master title style • Edit Master text styles • Second level

Click to edit Master title style • Edit Master text styles • Second level • Third level • Fourth level • Fifth level Compare between Fatty acids synthesis and oxidation 32

Click to edit Master title style • Edit Master text styles • Second level

Click to edit Master title style • Edit Master text styles • Second level • Third level • Fourth level • Fifth level

v. Alternative ways of oxidation Click to edit Master title style Ø( )Alpha-oxidation of

v. Alternative ways of oxidation Click to edit Master title style Ø( )Alpha-oxidation of FA • Edit Master text styles -For Branched-chain FA (phytanic • Second level acid, 20 C • Third in level brain): As its not a • Fourth level substrate for acyl Co. A • Fifth level dehydrogenase due to methyl group on its third (β) carbon. -It is based on the hydroxylation of alpha C then removal of C 1 as CO 2 (Decarboxylation) at a time from the carboxyl end of the FA. -It does not need Co. A. -It does not produce energy.

Click to edit Master title style -Refsum disease = A defect • Second level

Click to edit Master title style -Refsum disease = A defect • Second level alpha-oxidation results in accumulation of phytanic acid and production of neurological symptoms. • Edit Master text styles • Third level • Fourth level • Fifth level https: //youtu. be/p. Sdhbymf 6 Sk

v. Aternative ways of oxidation ClickØto( )Omega-oxidation edit Master title style of FA ω-Oxidation

v. Aternative ways of oxidation ClickØto( )Omega-oxidation edit Master title style of FA ω-Oxidation (in ER involving cytochrome p 450): Methyl • Edit Master text stylesto carboxyl group and Beta terminus is oxidized • Second level from both ends(dicarboxylic). Its a oxidation proceed • Third level minor pathway, its up-regulation in MCAD deficiency • Fourth level • Fifth level β α CH 3 –CH 2 -(CH 2)n-CH 2 -C 00 H CH 2 --CH 2 -(CH 2)n-CH 2 -C 00 H 0 H α β β α H 00 C—CH 2 -(CH 2)n-CH 2 -C 00 H Β-oxidation

Click to edit Master title style • Edit Master text styles • Second level

Click to edit Master title style • Edit Master text styles • Second level • Third level • Fourth level • Fifth level