Carbohydrate and Lipid Metabolism

Carbohydrate Metabolism

  • Recap from Yesterday:

    • Discussed carbohydrate metabolism in detail.
    • Identified components of biochemical pathways in carbohydrate metabolism.
    • Briefly talked about clinical disorders of carbohydrate metabolism.
    • Mentioned moving onto lipid metabolism.

  • Glycolysis and Gluconeogenesis:

    • Seven reactions are the same in both pathways, using the same enzymes.
    • Key regulatory steps involve irreversible reactions with different enzymes for glycolysis and gluconeogenesis.

  • Substrates for Gluconeogenesis:

    • Gluconeogenesis: Generation of new glucose from non-carbohydrate precursors.
    • Pyruvate: Product of Glycolysis, catabolism of glucogenic amino acids.
    • Lactate: Fits into metabolism through anaerobic fermentation.
    • Glucogenic Amino Acids: Most amino acids are glycogenic; some are purely ketogenic, and a few are both.
    • Citric Acid Cycle Intermediates: Produced through various pathways.
    • Propionate: Product of ruminant fermentation and odd-carbon fatty acids.

  • Propionate Significance:

    • Produced by bacteria in the gastrointestinal tract, especially in ruminants.
    • Derived from odd carbon fatty acids; catabolism leaves three carbons as propionate.

  • Summary:

    • Anything that breaks down to citric acid cycle intermediates or pyruvate can be used in gluconeogenesis, including glucogenic amino acids and propionate.
    • Glycerol from triacylglycerol catabolism can be a substrate in gluconeogenesis.

  • Lipid Breakdown:

    • Lipid breakdown can stimulate energy generation (electron transport chain and oxidative phosphorylation) and feed into gluconeogenesis.

  • Pyruvate and Mitochondria:

    • Gluconeogenesis occurs in the cytoplasm.
    • Pyruvate is typically transported into mitochondria.
    • Shuttle mechanisms allow pyruvate to move through mitochondria.
    • Pyruvate forms oxaloacetate, then malate, which is transported back out and reforms oxaloacetate.

  • Glucogenic Amino Acids:

    • Amino acids (pink boxes) break down into intermediates like citric acid cycle components or pyruvate, leading to phosphoenolpyruvate and glucose formation via gluconeogenesis.
    • Ketogenic amino acids (yellow) cannot be used as substrates for gluconeogenesis.
    • Protein breakdown can maintain glucose homeostasis.

  • Ruminant Fermentation:

    • Propionate and lactate, produced from cellulose and bacteria in the rumen, are substrates for gluconeogenesis.
    • Propionate conversion to oxaloacetate is complex, utilizing ATP and involving carbon dioxide fixation.
    • Regulatory steps require vitamin B12.

  • Reciprocal Regulation:

    • Glycolysis and gluconeogenesis are reciprocally regulated; only one pathway is active at a time in a cell.
    • Step three of glycolysis is critical. High AMP (low energy) stimulates glycolysis and inhibits gluconeogenesis.

  • Simultaneous Pathways:

    • In a whole animal, both glycolysis and gluconeogenesis can occur simultaneously in different tissues.
    • Example: Skeletal muscle undergoing anaerobic fermentation produces lactate, which the liver uses for gluconeogenesis (Cori cycle).

  • Regulation Details:

    • Glycolysis and gluconeogenesis can occur in all cells.
    • The switch between pathways isn't abrupt; down-regulation of one precedes up-regulation of the other.
    • Depends on metabolic needs and physiological context.
    • Example: Hepatocyte activates glycolysis post-meal consumption, transitioning to gluconeogenesis as glucose availability decreases.

  • Glycogen Overview:

    • Glycogen: Storage polysaccharide in animals found as granules in the cytoplasm.
    • Branched molecule in liver and skeletal muscle.
    • Regulates blood glucose concentration.

  • Glycogen Importance:

    • In muscles, it is broken down and used within the cells.
    • In the liver, it acts as a reservoir for glucose distribution to circulation.
    • Regulation of glycogen metabolism involves coordinated reciprocal regulation of enzymes.
    • Glycogen storage diseases are usually lethal due to disruption of glucose homeostasis.

  • Glycogen Breakdown:

    • Occurs in the cytoplasm.
    • Phosphorylase facilitates phosphorylation of glucose residues from glycogen, shortening glycogen by one residue and producing glucose-1-phosphate.
    • Continues until four residues away from a branch point.

  • Branch Points:

    • Phosphorylase stops four residues away from branch points.
    • Debranching enzymes linearize the branch so phosphorylase can continue.

  • Glycogen Synthesis:

    • Starts from glucose-6-phosphate.
    • Reversible reaction between glucose-6-phosphate and glucose-1-phosphate.
    • UDP-glucose is formed from UTP plus glucose-1-phosphate.
    • Condensation step: Formation of a glycosidic bond to the growing glycogen polymer.

  • Glycogen Synthesis Details:

    • UDP-glucose intermediate.
    • Condensation reaction via glycogen synthase adds to glycogen and releases UDP.

  • Reciprocal Regulation Summary:

    • Only one pathway occurs at a time within a cell.
    • Coordinated phosphorylation and dephosphorylation of key regulatory enzymes.
    • Phosphorylation of glycogen synthase inhibits its activity.
    • Phosphorylation of glycogen phosphorylase stimulates its activity.

  • Enzyme Coordination:

    • Single enzyme coordinates phosphorylation and dephosphorylation of both enzymes.
    • Protein phosphatase stimulates dephosphorylation, promoting glycogen synthesis and inhibiting glycogen degradation.

  • Hormonal Regulation:

    • Protein phosphatase one activity is regulated by hormones.
    • Adrenaline (epinephrine) stimulates glycogen breakdown and inhibits glycogen synthesis.
    • Glucagon stimulates degradation and inhibits synthesis when circulating blood glucose concentration is low.

  • Hormone Effects:

    • Glucagon works oppositely to insulin.
    • Insulin is secreted when there's lots of glucose, while glucagon is secreted when there's low circulating blood glucose.

  • Glycogen Storage Diseases:

    • Disruptions in glycogen metabolism lead to glycogen accumulation.
    • Disruptions are in glycogen breakdown or its regulation.
    • Can lead to hypoglycemia.
    • Usually inherited disorders or mutations in glycogen degradation enzymes.
    • Characterized by the enzyme affected and the organ impacted.
    • Types one through eight in humans, one, two, three, and eight in animals.
    • Liver is often the main tissue impacted.

  • Diabetes Mellitus:

    • Affects about 1% of dogs; different breeds have varying incidents.

  • Insulin:

    • Secreted from the pancreas.
    • Increases glucose uptake by cells by increasing glucose carrier proteins.
    • Some glucose transporters are insulin-sensitive, while others are not.

  • Disrupted Insulin Signal:

    • Problems in movement of glucose from circulation into cells.

  • Type One Diabetes:

    • Insulin-dependent, often occurs early in life and suddenly.
    • Damage to islet cells in the pancreas due to pancreatitis, autoimmunity, or toxins.
    • The signal for glucose to move into cells may be absent or significantly reduced.
    • Adaptive metabolism occurs to counteract this.
    • Symptoms: Very skinny, always hungry, polydipsia, polyuria, and ketotic.

  • Type Two Diabetes:

    • Insulin-independent; may require no or occasional insulin injections.
    • Often late and slow onset.
    • Animal overweight.
    • Insulin secretion may be reduced, or cells can become insulin-insensitive.

  • Pancreatic Islets:

    • These are discrete bundles of cells throughout the pancreas that secrete insulin.

  • Consequences of Increased Blood Glucose:

    • Hypertonicity of plasma, intracellular dehydration, hyperglycemic coma.
    • Accumulation of sorbitol, precipitation of proteins in the lens of the eye, and the formation of cataracts.

  • Consequences of Glucose Not Entering Cells:

    • Stimulation of gluconeogenesis.
    • Mobilization of protein and lipid to generate substrates for gluconeogenesis.
    • Protein catabolism leads to weight loss and weakness.
    • Lipid catabolism leads to weight loss from adipocytes and excess formation of ketone bodies, potentially leading to ketosis or ketoacidosis.

  • Hypoglycemia:

    • When there isn't enough glucose, resulting in low blood glucose concentration.
    • Behavioral changes, weakness, and neurological impact.
    • It can be from partial or total starvation or increased glucose demands (e.g., pregnancy).
    • Newborn piglets are particularly susceptible because their livers aren't fully developed.

  • Metabolic Acidosis:

    • Excess production of lactic acid or lactate, and ketoacidosis.
    • Depression of pH in general circulation.
    • Neurological impairment, depression, inactivity, recumbency, coma, and death.

  • Exertional Myopathy:

    • Accumulation of lactic acid due to exertion, particularly in large muscle bodies.
    • Stiffness in gait occurs.

Lipid Metabolism

  • Overview

    • Lipid metabolism: Mechanisms of lipid metabolism and biosynthesis, and components of biochemical pathways.
    • Topics: Fatty acid breakdown, fatty acid biosynthesis, ketogenesis.

  • Fatty Acids

    • Hydrophilic carboxylic acid head and a hydrocarbon tail.
    • Hydrocarbon tail mostly even number, but it can occasionally be an odd number.
      • Odd number leads to liberation of propionate, a substrate for gluconeogenesis.

  • Triacylglycerols

    • Glycerol and three fatty acids, which are esterified or through ester bonds.
    • Hydrophobic and they form unilocular fat droplets within the cytoplasm of cells like adipocytes.

  • Triacylglycerol Breakdown and Utilization

    • Occurs in adipocytes located in the abdomen or subcutaneous tissues.

  • Key steps

    • Lipolysis: Breakdown of the tricyclistrones into glycerol and fatty acids.
    • Fatty acid activation.
    • Transport of those fatty acids to mitochondria.
      • Carnitine shuttle is the mechanism by which the fatty acids are moved into mitochondria across the mitochondria membrane.
    • Specific pathway where we see degradation of those fatty acids.
      • Occurs in the mitochondria and is referred to as beta oxidation.
        • A major site for significant amounts of both energy generation, but also the release of reducing power, which can be utilized in ATP production.

  • Lipolysis

    • Hydrolysis of trisoglycerols with sequential removal of the fatty acids.
    • Catalyzed by what enzymes that are referred to as lipases or lipases.
    • Controlled by hormones so sometimes referred to as hormone-sensitive lipases.

  • Lipolysis Process

    • Triglycerides (trisylglycerols): Release a fatty acid, so we end up with a di glyceride or diacylglycerol.
    • Release of the second fatty acid.
    • Release of the third one
      • We see the release of glycerol.
    • Sequential removal of the fatty acids to release: Glycerol and three fatty acids.
      • Top part is really saying that the whole process is facilitated by hormones (adrenaline epinephrine or glucagon).
        • Domino effect or cascade effect of different activation events which eventually results in activation of key enzymes.
        • Mobilization of tricyclicals has effect on activating enzymes within the cell to facilitate breakdown.
        • Hormones will facilitate a glycogen breakdown as well.

  • Products of Lipolysis Utilization

    • Glycerol feeds into glycolysis, glycolysis, glycolysis
      • Little bit more to it that we'll touch on a little bit later when we talk about electron transport chain.
    • Fatty acid activation.

  • Fatty Acid Activation

    • Fatty acid plus ATP: Utilizing energy, plus coenzyme A, end up with what are called fatty A cell CoA molecules.
      • Fatty acid with coenzyme A stuck to it.
        • Thioester bond (sulfur in the molecule).
      • Coenzyme A almost acts like a little handle to move the fatty acids around.

  • Carnitine Shuttle System

    • Movement of fatty acid from the cytoplasm into the mitochondrial matrix.
      • Addition of the fatty acid component to a molecule called carnitine.
        • Then in a media is referred to as acyl carnitine, and it's the acyl carnitine which is translocated across the mitochondrial membrane.
        • Then see dissociation and return or translocation of return of the carnitine.
          • Carnitine is almost acting like a shuttle to move the fatty acid, through, across the mitochondrial membrane, releasing it, and then returning back to the cytoplasm.

  • Beta Oxidation

    • Sequential removal of two carbons at a time.
    • Shown as a cyclical process, Fatty acid might come in with 16 carbons in the hydrocarbon tail. It enters beta oxidation, it leaves with 14.
    • Moves through beta oxidation again ends up with 12 all the way until there's only two left.
      • Sequential chipping off two of those carbon blocks, which is an acetyl group.
      • End up with lots of acetyl CoA.

  • Energetics

    • For each cycle of beta oxidation, 1 molecule of acetyl CoA, 1 molecule of NADH, 1 molecule of FADH.
    • Each carbon molecule produces 7 ATP, whereas Glucose per carbon produces 5.3 of ATP.
      • Therefore Lipids produce more energy per molecule than carbohydrates.

  • Water Production

    • Lipids can produce HO for the completion of lipid oxidation.

  • Gluconeogenesis

    • Fatty acids, can't be used for gluconeogenesis (only exception for odd numbers of carbons).

  • Fatty acids and Glucose link

    • Protein: As the substrate, organic substrate for gluconeogenesis.
    • Lipid: As the energy source for gluconeogenesis.

  • Unsaturated Fatty Acids

    • Unsaturated fatty acids must undergo a few extra steps to produce energy.

  • Fatty Acid Biosynthesis Overview

    • Fatty Acid Oxidation: Occurs in the mitochondria, handle is Coenzyme A, two carbon units removed at a time, product is Acetyl CoA, FADH and NADH is liberated, and the enzymes are separate.
    • Fatty Acid Synthesis: Occurs in cytoplasm, handle is Acyl Carrier Protein, carbons added two at a time, Malonyl COa is the substrate, NADPH is the resulting, enzyme acts as a big bunch of enzymes that work together.

  • Acyl Carrier Protein vs Coenzyme A

    • Acyl Carrier protein and Coenzyme A are very similar, but one contains enzymes and one contains a nucleotide component.

  • Acetyl CoA and Cytoplasm relationship

    • Acetyle CoA can move via a shuttle mechanism (Citrate Transport System) and provides a relationship between the activity of the Citric Acid cycle and Fatty acid biosynthesis.

  • Citrate Transport System

    • Oxaloacetate and pyruvate create condensation and form a citrate reaction.
    • From citrate moves back out to the cytoplasm (Through inner Mitochondrial Membrane).
      • This moves Acetyl CoA out to the cytoplasm.
    • This also generates energy in the form of NADPH (used in Fatty acid Bio Synthesis)

  • Malonyl CoA Formation

    • Formed from Acetly CoA
    • Uses Bicarbonate and ATP to create Malonyl CoA.

  • BioSynthesis pathway of fatty acids

    • Loading with loading CoA as the catalyst which uses two carbons from the acetly group and two carbons from the mananyl molecule.
      • Bond then needs to be rearranged which happens in all of the other steps that remove double bonds and add the chains.
        • Another Malonyl CoA molecule Gets attached and carbon dioxide is removed each Time.

  • Chemical reaction of fatty acids and molecules formula

    • Acetly CoA plus 7 Malonyl CoA creates 1 Paltimic Acid with some excess molecules.

  • Molecules for energy formula

    • To create C16, 8 Molecules are needed while other Molecules are needed for the pentose Phosphate Pathway.

  • Hormone relation to Lipids

    • Adrenaline Glucagon relationship breakdown lipids.

  • Adrenaline, Glucagon, Insulin relationship and summary overview.

    • When there is a low circulating blood glucose and a low energy, Adrenaline and Glucagon are used breakdown of lipids and creates a source called oxidation.
    • When there are high levels of Glucose, Insulin is used stimulate Fatty acid bio synthesis with a range of mechanisms.
      • This relationship causes intermediates and regulatory actions.