ENERGY SUPPLY TO HEART-1 DR. SAIDUNNISA, M.D Professor and chairperson Department of Biochemistry

LEARNING OUTCOMES At the end of the session the student shall be able to:  Must know: 1.Mention the different sources of energy for heart and elucidate the process by which they are synthesized. 2.Appraise the steps of adipose fat made available as source of energy for myocardial contraction and mention the disorders related to fatty acid oxidation.  Need to know 1.Relate the minor pathways of fatty acid oxidation (Alpha, omega and peroxisomal oxidation) in energy generation.

CARDIAC MUSCLE CELLS  The cardiac cells are striated and they are regulated involuntarily (we do not have to think about making our heart beat).  Cardiac muscle cells are designed for endurance and consistency.  They depend on aerobic metabolism for their energy needs because they contain many mitochondria and very little glycogen.  These cells thus generate only a small amount of their energy from glycolysis using glucose derived from glycogen.

FUEL UTILIZATION IN CARDIAC MUSCLE (NORMAL CONDITIONS) (FATTY ACIDS)  The heart primarily uses fatty acids (60–80%), lactate, and glucose (40–20%) as its energy sources.  98% of cardiac ATP is generated by oxidative pathway (fatty acid oxidation) ; 2% is derived from glycolysis.  However, ketone bodies are not a preferred fuel for the heart, because the heart prefers to use fatty acids.

FUEL UTILIZATION IN CARDIAC MUSCLE (NORMAL CONDITIONS) (LACTATE)  Lactate generated by red blood cells is used by the heart, it is oxidized to carbon dioxide and water, following the pathway lactate to pyruvate, pyruvate to acetyl-coA, acetyl CoA oxidation in the TCA cycle, and ATP synthesis through oxidative phosphorylation.

FUEL UTILIZATION IN CARDIAC MUSCLE (NORMAL CONDITIONS) (GLUCOSE)  Glucose transport into the cardiocyte occurs via both GLUT1 and GLUT4 transporters, although approximately 90% of the transporters are GLUT4.  Insulin stimulates an increase in the number of GLUT4 transporters in the cardiac cell membrane.

ADIPOSE TISSUE TRIACYLGLYCEROL (TAG)  Adipose tissue TAG is derived from two sources: 1.Dietary lipids 2.TAG synthesized in liver  Fatty acids are released from adipose tissue TAG stores: 1.Between meals, (during overnight fasting ) 2.During periods of increase demands like exercise and starvation.

WHAT PURPOSE DOES FATTY ACID METABOLISM SERVE IN HUMANS ?  Fatty acid oxidation in mitochondria is responsible for providing energy to cells when glucose levels are low, Examples 1.Starvation 2.Diabetes mellitus  (Gluconeogenesis is dependent on fatty acid oxidation, any impairment causes hypoglycemia).

TERMINOLOGY  Acetyl CoA: combination of Acetic acid + Co-enzyme A  Acyl CoA: combination of Fatty acid + Co-enzyme A

FATTY ACID OXIDATION  Takes place in mitochondria by most of the tissues in the body.  Is an aerobic process, requiring the presence of oxygen.  Major fatty acids oxidized are LCFA as they are highest in dietary lipids (Palmitic acid, stearic acid)  (Brain, RBC and adrenal medulla cannot use fatty acids for energy requirement).

CLASSIFICATION  Fatty acids shorter than 12 carbons can cross the inner mitochondrial membrane with out the aid of transporter (Carnitine).  Short chain: 2-6 carbons  Medium chain: carbons  Long chain: >16 carbons  Very long chain: >20 carbons

ΒETA-OXIDATION  Fatty acids in the body are mostly oxidized by β-oxidation.  Definition:  β-oxidation is defined as oxidation of fatty acids on the β-carbon atom.

 In β-Oxidation 2 carbons are cleaved at a time from fatty acid (acyl CoA) molecules starting at the carboxyl end.  The chain is broken at α (2 c) and β (3 c) carbon atoms hence the name β- oxidation.  The 2 carbon units formed are acetyl CoA.

ΒETA -OXIDATION  β -Oxidation involves 3 stages: 1.Activation of fatty acids occurring in the cytosol. 2.Transport of fatty acids into the mitochondria. 3.β-oxidation proper in the mitochondrial matrix.

ACTIVATION OF FATTY ACID  In the cytosol, Acyl- CoA synthetase in the presence of ATP coverts fatty acid to FA acyl CoA (active fatty acid ).

CARNITINE SHUTTLE  A specialized carrier carnitine transports the activated long chain fatty acid (acyl CoA) from the cytosol into the mitochondrial matrix.  Carnitine is β-hydroxy gamma trimethyl ammonium butyrate.  Sources of Carnitine: found primarily in meat products.  It is synthesized from the amino acids methionine and lysine in liver and kidney and is abundantly present in muscle.

ACTIVATED FATTY ACID TRANSPORTATION

INHIBITORS OF CARNITINE SHUTTLE  Carnitine Palmitoyl Transferases I and II are inhibited by malonyl-CoA, an intermediate of fatty acid synthesis.

CAT-I AND CAT-II DEFICIENCY: CLINICAL SYMPTOMS  Inability to use LCFA for fuel can lead muscle weakness with myoglobinemia and myoglobunuria following prolonged exercise.  Severe hypoglycemia on long fast leading to coma and death.  Treatment: Avoidance of prolonged fasts. Diet high in carbohydrates low in LCFA. Supplemented with SCFA & MCFA and Carnitine.

ΒETA -OXIDATION PROPER ( PALMITIC ACID EVEN CHAIN SATURATED FA)  Involves 4 steps: 1.Dehydrogenation/oxidation 2. Hydration 3.Dehydrogenation/oxidation 4. Cleavage 1.FAD-dependent dehydrogenation 2.Hydration (H20) 3.NAD-dependent dehydrogenation 4.Thiolytic cleavage (SCOA)

ΒETA –OXIDATION STEPS

ENERGETICS  One cycle of β-oxidation results in:  Removal of 2 Carbons as acetyl CoA  Formation of one NADH + H +  Formation of one FADH2

ENERGETICS  Complete oxidation of 1 molecule of palmitoyl- CoA produces : 1.8 acetyl CoAs 2.7 NADH + H+ 3.7 FADH2 4.7cycles of β- oxidation

ENERGETICS

REGULATION OF FATTY ACID OXIDATION  FA metabolism is under hormonal regulation:  In fasting when fuel levels are low, Epinephrine and Glucagon stimulate β- oxidation.  During the fed-state, Insulin, which is secreted it inhibits β-oxidation.

DISORDERS ( SUDDEN INFANT DEATH SYNDROME) 1.SIDS or Reye syndrome : sudden infant death syndrome is due to deficiency of medium chain acyl CoA Dehydrogenase. MCFA are plentiful in human milk.  It is an Autosomal recessive disorder.  Decrease fatty acid oxidation and hypoglycemia.  Treatment: carbohydrate rich diet.

DISORDERS JAMAICAN VOMITING SICKNESS 2. Jamaican vomiting sickness: severe hypoglycemia, vomiting, convulsions, coma and death.  It is caused by eating unripe ackee fruit which contains toxin hypoglycin which inhibits short and medium chain acyl CoA dehydrogenase and β-oxidation.

ACKEE FRUIT  The fruit was imported to Jamaica from West Africa.

OXIDATION OF ODD-NUMBERED CARBON ATOMS  Proceeds in same manner as even only difference in the final round of β-oxidation yields acetyl-CoA & propionyl-CoA.  Even chain FAs are not substrates for GNG.  Propionyl CoA: converted to succinyl Co enters GNG via TCA.

OXIDATION OF UNSATURATED FATTY ACIDS  Due to presence of double bonds two additional enzymes -an isomearse and an epimerase are required other reactions are the same.  Provide less energy than saturated FA.

VLCFA OXIDATION  VLCFA ( more than carbons) are oxidized in Peroxisomes.  Zellweger syndrome is due to inherited absence of Peroxisomes, VLCFA accumulate in brain, liver,kidney also called cerebrohepatorenal syndrome.  β-oxidation occurs in a modified form reducing equivalents are not transferred to ETC but directly handed over to O 2. resulting in formation of H 2 O 2 which is cleaved by catalase.

ALTERNATE ROUTES OF FATTY ACID OXIDATION  Fatty acids that are not readily oxidized by the enzymes of β- oxidation enter alternate pathways of oxidation. 1.α-oxidation 2.ω-oxidation

ΑLPHA-OXIDATION  Which involves removal of one carbon at a time from the carboxyl end of the molecule.  Site: Brain tissue  Disorder: inherited autosomal recessive disorder of α-oxidation leads to Refsum’s disease.  It is a rare neurological disorder, this is due to accumulation of unusual FA Phytanic acid due to deficiency of phytanic acid α-oxidase.

OMEGA-OXIDATION  FA undergo oxidation at the carbon atom farthest i.e ω-carbon.  This is brought about by hydroxylase enzymes involving cyto P-450 in endoplasmic reticulum.  Site: Brain tissue.

LIPOPROTEIN LIPASE  LPL is an extracellular enzyme anchored by heparan sulfate to the capillary walls of most tissues predominantly adipose tissue, cardiac and skeletal muscle converts the TAG of Chylomicrons and VLDL to fatty acids and glycerol.  The highest concentration of LPL in cardiac muscle reflects the use of fatty acids to provide more energy needed for cardiac function.

ENERGY SUPPLY TO HEART-2

ENERGY : A VITAL NEED FOR HEART  Each day, the heart beats about times and pumps approximately 10 metric tones of blood through the body.  To achieve this, the heart needs more energy than any other organ in the body.  It cycles through about 6 kg of ATP every day – 20 to 30 times its own weight.  Mitochondria are the site of energy production, their volume represents 30% of myocardial cell volume.

NORMAL CONDITIONS  To acquire the energy necessary to carry out its function, the heart mainly relies on oxidative metabolic pathways.  Converts the chemical energy stored in fatty acids and glucose into ATP that provides the mechanical energy for the actin-myosin interaction of myofibrils.  The heart also derives its energy from other sources such as lactate, pyruvate, and ketone bodies, but to a much lower extent.

IN SITUATIONS OF ISCHEMIA  Fatty acid oxidation and glucose oxidation both decrease due to oxygen shortage, and anaerobic glycolysis becomes a more important source of energy as it is the only process capable of producing ATP in the absence of oxygen.  However, ATP generated by glycolysis is not sufficient to meet the energy needs of the beating heart, resulting in a decline in total ATP and energy production of the heart.

IN SITUATIONS OF ISCHEMIA  In response to catecholamine release, FFA levels increase and free fatty acid oxidation becomes the main oxidative pathway producing high levels of acetyl-coenzyme A, which negatively feedback inhibit PDH activity and thus pyruvate oxidation.  The nonoxidized pyruvate is converted into lactate and protons (H+), which gradually induce cellular acidosis (a fall in pH) and calcium overload results in ATP decrease and NADH increase resulting in inefficient contraction of the heart.

IN Anaerobic Glycolysis Protons Intracellular calcium and sodium ATP synthesis Cardiac efficiency Mitochondrial oxidation IN SITUATIONS OF HEART FAILURE

LEARNING CHECK!!!  A 25 year old decides to train for the marathon by running 12 miles three times per week. He is now 13 pounds over his ideal weight, and he plans on losing this weight. He considers a variety of dietary supplements to increase his endurance and selects one containing………  Carnitine, CoQ, pantothenate, riboflavin, and creatine.

LEARNING CHECK!!!  Can β-oxidation of fatty acids occur in red blood cells?  RBC lack mitochondria,

LEARNING CHECK!!!  At which one of the periods listed below will fatty acids be the major source of fuel for the tissues of the body? (A) Immediately after breakfast (B) Immediately after dinner (C) While running the first mile of a marathon (D) While running the last mile of a marathon