Metabolism of dietary lipids Biochemistry Department

© I L O Intended Learning Outcomes By the end of this lecture, the student should be capable of: 1.Recognizing the different types of fatty acid synthesis and oxidation. 2.Finding the role of storage of fatty acid as TAG 3.Identifying the fatty acid synthesis and degradation 4.summarizing the synthesis and oxidation processes of fatty acids. 5.explaining the modes of regulation for TG & FA metabolism 6.Describing some abnormalities in lipid metabolism

Fatty Acids And Triacylglycerol Metabolism

Fatty acid synthesis Storage of FA as TAG (Lipogenesis) Mobilization of stored fat (lipolysis) Fatty Acid Oxidation Metabolism of ketone bodies Fatty Acids And Triacylglycerol Metabolism

Mobilization of Stored Fats (lipolysis) ready for Oxidation of Fatty Acids highly reduced and largely anhydrous. TAGs provide concentrated stores of metabolic energy because they are highly reduced and largely anhydrous. The yield from complete oxidation of fatty acids to CO2 and H2O is nine kcal/g fat (as compared to four kcal/g protein or carbohydrate, Mobilization of stored fat (lipolysis)

The hydrolytic release of FAs and glycerol from TAG is initiated by hormone-sensitive lipase (HSL), which removes 1FA from C1 and/or C3 of TAG. Additional lipases specific for DAG or MAG remove the remaining FAs. TAGTAG Or DAG or MAG Activation of hormone sensitive lipase to Release fatty acids from TAG 1-HSL

HSL is activated by: epinephrine or glucagon, and others. It is phosphorylated by a 3',5'-cAMP dependant protein kinase and vice Versa by insulin & glucose.

- HSL is similar to glycogen acetyl phosphorylase but reverse to Acetyl CoA carboxylase. -When cAMP-cascade is activated, fatty acid synthesis is turned off & TAG degradation is turned on.

Adenylyl Cyclase Phosphodiestrase ATP cAMP 5`AMP Epinephrine& Norepinephrine Insulin, PG E1, nicotinic acid ACTH, TSH, glucagonGH Thyroid H + - PPi cAMP dependant protein kinase + Insulin Methyl xanthines e.g. caffeine - +

GPDH By blood Glycerokinase Glycerol Glycerol-3P ATPADP Mg Glycolysis Gluconeogensis DHAP TAG By the Liver Only Fate of glycerol In Adipose Tissues: Glycerol must go to the liver? (no Glycerokinase). Fate of Fatty Acids FFA ALB Enter tissue cells(?) to be activated to Acyl- CoA ready for Oxidation to give energy FFAs moves from adipocyte cell membrane Immediately in plasma Remember: Regardless blood levels of plasma FFA cannot be used as fuel by erythrocytes(no mitochondria) or by the brain (impermeable blood-brain barrier).

Brown Adipose Tissue: Is for heat production in new born & hibernating animals but absent in obese persons. Ch Ch : -  blood supply +  mitochondria &cytochromes -Low activity of ATP synthase -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.

Fatty Acid Oxidation  1-(  )Beta-oxidation of FA  Activation of FA  Transport of LCFA into mitochondria: (Carnitine shuttle-carnitine sources-carnitine deficiency)  Entery of short and medium chain FA?  Steps of oxidation  Energetics of oxidation  Oxidation of unsaturated FA  Oxidation of odd-number FA   -oxidation in peroxisome for very long chain FA.  2-Aternative ways of oxidation  (  )Alpha-oxidation of FA  (  )Omega-oxidation of FA

- In mitochondria matrix. -Even FA-> (-2C)  acetyl CoA+ NADH+ FADH2 -Odd FA ->1 propionyl CoA(3C) & (n) acetyl CoA. -Each cycle produces 5ATPs. - Even FA can produces only acetyl CoA, that cannot give glucose but Propionyl CoA is glucogenic. B. β-Oxidation of fatty acids (major catabolic path.) Activation of LCFA in the cytoplasm utilizing ATP occurs: First Step

-Carnitine shuttle to allow LCFA to enter the matrix (as inner mitochondrial membranes are impermeable to CoA). -FAs < 12C(e.g milk) passes without the aid of the shuttle. They are activated to their CoA derivatives by matrix enzymes for oxidation. The activated FA needs to go to the mitochondrial matrix How? Transport of acyl CoA into mitochondria: (Carnitine shuttle)

LCFA transport (Carnitine Shuttle): 1- Acyl group transferred from CoA to carnitine by carnitine palmitoyltransferaseI(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 CoA in the matrix; regenerating free carnitine.

Sources of carnitine: 1-diet ( meat products). 2- Endogenous synthesized carnitine (lysine and methionine) by liver &kidney but not in 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.

Carnitine deficiencies results in a decreased ability of tissues to use LCFA as a metabolic fuel. CPT-I deficiency ( liver) 1ry carnitine deficiency: =Congenital deficiencies in any of CPT system. CPT-II deficiency (cardiac & skeletal ms) Inability to use LCFA for fuel impairs the ability to synthesize glucosein fast.This leads to: severe hypoglycemia,coma, & death Cardiomyopathy to muscle weakness with myoglobinemia following prolonged Exercise.

2ry carnitine deficiency Liver disease Patients (decreased synthesis of carnitine). Increased requirement for carnitine ( pregnancy, severe infections, burns, or trauma.) Malnutrition patients (vegetarian) Hemodialysis patients (removes carnitine from the blood) Treatment includes: avoidance of prolonged fasts, diet high in carbohydrate and low in LCFA, but supplemented with medium-chain fatty acid and, in cases of carnitine deficiency, carnitine.