1011 Week 12 Lecture

Metabolic Processes Overview

• The unit has covered exergonic metabolic processes for energy production and endergonic reactions for energy utilization.

• The focus shifts to the metabolic activities within individual tissues and organs and how these integrate within the body.

Integration of Metabolic Processes

• The lecture integrates metabolic processes discussed in previous topics (C and D) to provide a comprehensive metabolic picture.

Tissue-Specific Metabolism: Liver

• The liver is the primary organ in metabolism.

• It prioritizes the needs of other tissues and is the initial destination for consumed nutrients.

• It is a central, distributory organ, highly sensitive to the needs of other tissues.

Adipose Tissue

• Adipose tissue stores lipids in the form of triacylglycerol (TAG).

• It serves as an energy reserve due to its capacity to store TAG.

Muscle Tissue

• Muscle tissue, especially skeletal muscle, requires a lot of ATP due to constant contraction and relaxation.

• It both produces and utilizes ATP to perform mechanical work.

• Cardiac muscle differs from skeletal muscle; it is continuously active and has constant energy demands.

Brain

• The brain is crucial for generating impulses.

• It relies heavily on glucose availability.

Red Blood Cells

• Red blood cells are also important in metabolism, though not as extensively discussed in this lecture.

Nutrient Processing and Transport

• Food (carbohydrates, lipids, proteins) is digested into monomers: glucose, amino acids, and fatty acids.

• These monomers are absorbed by enterocytes (intestinal cells).

• Glucose and amino acids are absorbed directly into the blood, while fatty acids are reprocessed into triacylglycerol (TAG).

• Absorbed substances are transported to the liver; glucose and amino acids via the blood, and reprocessed fatty acids (TAG) via the lymphatics.

• Post-meal, the liver is saturated with these nutrients.

Liver's Sensitivity and Response

• The liver assesses and distributes nutrients based on the needs of other tissues and the body's circumstances.

• It responds to fasting or well-fed states.

• The liver adapts its enzymatic activity based on diet composition (high-carbohydrate or high-protein).

Glucose Metabolism in the Liver

• Upon entering the liver, glucose is phosphorylated to glucose-6-phosphate.

• Phosphorylation commits glucose to metabolism.

Fates of Glucose-6-Phosphate

• Dephosphorylation:

  • In cases of low blood glucose, glucose-6-phosphate is dephosphorylated to release glucose into the bloodstream to maintain blood glucose levels.

• Glycogenesis:

  • In a well-fed state, excess glucose is stored as glycogen via glycogenesis.

• Glycolysis:

  • If there's a need for energy, glucose-6-phosphate enters glycolysis, producing pyruvate.

  • Pyruvate enters the mitochondria and is oxidized to acetyl CoA.

  • Acetyl CoA is oxidized via the citric acid cycle, generating reduced electron carriers.

  • These carriers donate electrons to the electron transport chain, leading to ATP synthesis.

• Acetyl CoA Fates:

  • Acetyl CoA can be oxidized via the citric acid cycle.

  • In the well-fed state, it stimulates cholesterol, fatty acid, and triacylglycerol (TAG) biosynthesis.

• Pentose Phosphate Pathway:

  • Glucose-6-phosphate can enter the pentose phosphate pathway.

  • This pathway oxidizes glucose without producing energy.

  • It generates NADPH, essential for fatty acid synthesis, and a five-carbon precursor for DNA and RNA synthesis.

Amino Acid Metabolism in the Liver

• Liver proteins have short lifespans and are continuously renewed.

• The amino acid pool in the liver is replenished from various sources.

Fates of Amino Acids

• Protein Synthesis:

  • In the well-fed state, amino acids synthesize liver proteins or plasma proteins.

  • Amino acids are exported to other tissues for tissue-specific protein synthesis.

• Synthesis of Specialized Macromolecules:

  • Amino acids are used to synthesize nitrogen-containing macromolecules like hormones, nucleotides, and porphyrins.

• Catabolism:

  • Amino acids cannot be stored, so excess amino acids are catabolized.

  • The amino group is separated, and the remaining carbon skeleton is processed.

  • Amino groups are converted to urea via the urea cycle.

  • The remaining molecule is converted to pyruvate.

Pyruvate's Role and Fates

• Pyruvate can be used to synthesize glucose via gluconeogenesis during starvation, which then is released into the blood.

• If energy is needed, pyruvate is oxidized to acetyl CoA, entering the citric acid cycle for ATP production.

• Acetyl CoA can synthesize fatty acids under well-fed conditions or, during fasting, citric acid cycle intermediates can be precursors for gluconeogenesis.

• The glucose goes out in the blood and potentially can be transferred to the muscle where it can undergo glycogen synthesis.

Lipid Metabolism in the Liver

• Fatty acids in the liver are used for synthesizing liver-specific lipids.

Fatty Acid Metabolism

• Beta-Oxidation:

  • Fatty acids undergo beta-oxidation in the mitochondria to form acetyl CoA.

  • Acetyl CoA enters the citric acid cycle for oxidation.

  • Reduced electron carriers transfer electrons to the electron transport chain, leading to ATP synthesis.

• Ketone Body Synthesis:

  • During starvation/fasting, acetyl CoA can synthesize ketone bodies, which are exported to extrahepatic tissues.

• Cholesterol Synthesis:

  • In a well-fed state with excess acetyl CoA, cholesterol synthesis is stimulated.

• Plasma Lipoprotein Synthesis:

  • Excess fatty acids synthesize plasma lipoproteins for transporting triacylglycerol (TAG) and cholesterol.

• Release as Free Fatty Acids:

  • Excess fatty acids can be released into the blood as free fatty acids, bound to albumin.

Summary of Fatty Acid Fates

• Synthesize liver lipids.

• Oxidized to produce ATP.

• Serves as a precursor to synthesize ketone bodies.

• Synthesize cholesterol.

• Synthesize phospholipids and triacylglycerol (TAG).

Conclusion

• The liver's metabolic processes depend on the needs of the cells and the body's circumstances.

• Lipid, amino acid, and glucose metabolism can be adapted to various conditions, ensuring efficient resource allocation and energy production.

Adipose Tissue: Synthesis, Storage, and Mobilization of Triacylglycerol

Learning Outcomes for Part B

• Metabolic activities in adipose tissue.

Types of Adipose Tissue

• White Adipose Tissue:

  • Larger cells.

  • Contain one large lipid droplet.

  • Mitochondria, nucleus, and other organelles are pushed to the periphery.

• Brown Adipose Tissue:

  • Smaller cells.

  • Contain several lipid droplets.

  • High concentration of mitochondria, giving it a brown color.

Illustration of Adipocytes

• White adipocytes have a single large lipid droplet.

• Brown adipocytes have small, scattered lipid droplets within the cytoplasm.

Functions of Adipose Tissues

• White Adipose Tissue:

  • Fuel storage (storehouse of triacylglycerol).

  • Metabolically active.

• Brown Adipose Tissue:

  • Expresses thermogenin, a protein on the inner mitochondrial membrane.

  • Thermogenin dissipates the proton motive force.

  • Inhibits ATP synthesis.

  • Energy meant for ATP synthesis is released as heat (thermogenesis).

  • Important for keeping organs warm in low temperatures.

  • Found primarily in newborns and hibernating animals.

Glucose Metabolism in Adipose Tissue

• Adipocytes have active glycolysis.

  • Glucose is rapidly oxidized to pyruvate.

  • Pyruvate is oxidized to acetyl CoA.

  • Acetyl CoA is completely oxidized to CO2 and H2O, producing ATP.

Conversion of Glucose to Fatty Acids

• High carbohydrate consumption leads to glucose conversion to fatty acids at two instances:

  • Glycerol-3-phosphate formation:

    • Glycerol-3-phosphate condenses with fatty acids to form triacylglycerol.

  • Acetyl CoA formation:

    • Acetyl CoA leads to the production of fatty acids (as seen in part A).

Triacylglycerol Storage

• Adipose tissue stores excess triacylglycerol.

  • Triacylglycerol can be synthesized in the liver and exported to adipose tissue.

  • Triacylglycerol can be from excess consumption of a lipid-rich meal.

Lipolysis and Fatty Acid Release

• Triacylglycerol is stored until there is a demand for fuel (e.g., between meals).

• Lipases hydrolyze triacylglycerol to release free fatty acids.

• Free fatty acids are released into the circulation.

• Transported to other tissues (e.g., muscles, cardiac muscles).

Skeletal and Cardiac Muscle: Integration of Metabolism (Part C)

Overview

• Skeletal muscle: Uses ATP generated both aerobically and anaerobically for mechanical work.

• Cardiac muscle: Uses ATP generated aerobically to pump blood.

Muscle Cell Specialization

• Muscle cells are specialized to produce ATP, which is utilized for muscle cell contraction.

• Muscles work intermittently, adapting to varying demands.

  • Can be bursts of activity (short-lived).

  • Can be prolonged, less intense activity.

Oxygen Consumption

• At rest, muscles account for approximately 30% of the body's oxygen consumption.

• During activity, muscles can consume up to 90% of the total body's oxygen requirement.

Types of Muscle Cells (Myocytes)

Slow-Twitch Myocytes

• Richly supplied by blood vessels.

• High concentration of mitochondria.

• Energy production via oxidative phosphorylation.

Fast-Twitch Myocytes

• Fewer mitochondria and lower oxygen delivery.

• Rapid ATP consumption.

• Fatigue faster (due to high demand and reduced oxygen supply).

Energy Sources for Muscle Activity

At Rest

• Primary energy source: Fatty acids and ketone bodies.

  • Fatty acids from adipose tissue.

  • Ketone bodies from the liver.

• Both are oxidized aerobically to produce ATP.

Lightly Active Muscle

• Uses fatty acids, ketone bodies, and blood glucose.

• Glucose is oxidized via glycolysis to pyruvate, then converted to acetyl CoA, and enters the citric acid cycle for ATP production.

During Bursts of Heavy Activity

• High ATP demand exceeds the supply from aerobic metabolism alone.

• Muscle relies on muscle glycogen.

• Glycogen is broken down to lactate under anaerobic conditions.

Post-Vigorous Activity

• Rapid breathing indicates the need for extra oxygen.

• Oxygen used for oxidative phosphorylation to replenish ATP.

• ATP is used to synthesize glucose via gluconeogenesis.

  • Lactate (produced under anaerobic conditions) is utilized.

  • Muscle glycogen concentration is restored.

Cori Cycle: Metabolic Cooperation

• Demonstrates cooperation between skeletal muscle and the liver.

• Following intense activity:

  • Glycogen is broken down to lactate under anaerobic conditions along with ketone bodies and free fatty acids.

  • Lactate is transported to the liver via the blood.

  • In the liver, lactate undergoes gluconeogenesis to produce glucose.

  • Glucose is returned to the muscles via the blood to replenish glycogen stores.

Cardiac Muscle Differences

• Heart is continually active, unlike intermittent skeletal muscle contractions.

• Cardiac muscle relies entirely on aerobic metabolism.

  • Lack of oxygen (e.g., myocardial infarction) has serious consequences.

• Heart has negligible energy stores (glycogen and lipids).

• Uses glucose, free fatty acids, and ketone bodies as fuel sources.

• Primary fuels: Fatty acids and ketone bodies, followed by glucose.

Brain Metabolism

• The brain consists of neurons and glial cells.

• It accounts for approximately 20% of the body's oxygen consumption.

• The primary energy source for the brain is glucose.

  • The brain uses as much as 130 grams of glucose per day.

• The brain can also use ketone bodies (beta-hydroxybutyrate).

• ATP is required to maintain the electrical potential across neuron membranes, which is essential for signal transmission.

Fuel Utilization by Brain Cells

• Availability of Glucose: If glucose is available, it is the preferred energy source.

• Starved or Fasted State: Brain cells adapt to using ketone bodies.

  • Ketone bodies can cross the blood-brain barrier.

  • Brain cells oxidize ketone bodies to produce ATP.

• ATP is critical for:

  • Maintenance of transporters.

  • Electrogenic transport.

  • Generating membrane potential required for information transfer.

Glucose Oxidation in Brain Cells

• Glucose undergoes complete oxidation via glycolysis to pyruvate.

• Pyruvate is converted to acetyl CoA.

• Acetyl CoA is completely oxidized in the citric acid cycle to produce ATP.

Red Blood Cell Metabolism

• Red blood cells lack organelles such as nuclei and mitochondria.

• They cannot synthesize ATP or oxidize fatty acids.

• Red blood cells rely on glucose as their primary energy source.

• They are capable of carrying out anaerobic metabolism.

• Glucose is metabolized via:

  • Glycolytic pathway

  • Pentose phosphate pathway

• Red blood cells have the highest specific rate of glucose utilization of any cell in the body.

Part E: Integration of Metabolism

• Learning Outcomes:

  • Maintenance of blood glucose levels requires the combined actions of hormones like insulin, glucagon, epinephrine, and cortisol.

  • These hormones affect tissues such as the liver, muscle, and adipose tissue.

  • Focus will be on insulin and glucagon.

Insulin

• Insulin levels are high when blood glucose levels are higher than necessary.

• Cells take up excess glucose and convert it to storage forms like glycogen and triacylglycerol.

• Produced in the pancreas by the islets of Langerhans.

• Stimulates the conversion of glucose to storage fuel molecules.

• Promotes uptake of glucose by muscle cells and adipocytes.

  • In muscle cells, glucose is converted to glycogen.

  • In adipocytes, glucose is oxidized to acetyl CoA, which is a building block for fatty acids and triacylglycerol.

• In the liver:

  • Stimulates glycogen synthesis by activating glycogen synthase.

  • Inactivates glycogen phosphorylase (key enzyme in glycogen mobilization).

  • Stimulates fatty acid synthesis by converting acetyl CoA to triacylglycerol.

  • Triacylglycerol is exported from the liver and transported to adipocytes.

  • Stimulates the assembly of triacylglycerol in adipocytes.

Metabolic Effects of Insulin

• Increases glucose uptake by muscle cells and adipocytes by upregulating the production of the GLUT4 transporter.

  • GLUT4 transporter is externalized to bind and transport glucose.

• Increases glucose uptake by liver cells by increasing the expression of glucokinase (an enzyme of the glycolytic pathway).

• Promotes glycogen formation in the liver and muscle cells by stimulating glycogen synthase and inhibiting glycogen phosphorylase.

  • Insulin promotes glycogen formation while inhibiting glycogen breakdown.

• Stimulates glycolysis and the production of acetyl CoA, leading to increased triacylglycerol synthesis.
  Target enzyme: acetyl CoA carboxylase.

Insulin's Effect on Glucose Uptake and Glycogen Formation in Muscle Cells

• Insulin binds to the insulin-specific receptor on the surface of the muscle cell and stimulates the synthesis of the GLUT4 transporter.

• GLUT4 transporter appears on the surface of the muscle cell, facilitating glucose uptake.

• Once internalized, glucose is metabolized by hexokinase, which phosphorylates glucose and channels it towards the synthesis of glucose-6-phosphate, glucose-1-phosphate, and uridine diphosphate glucose, leading to glycogen formation.

• Insulin stimulates hexokinase and glycogen synthase, directing glucose towards glycogen formation.

• At the reaction level, insulin stimulates glycogen synthase, adding a glucose unit to the growing glycogen chain.

• At the same time, insulin inactivates glycogen mobilization by activating an enzyme that inactivates phosphorylase A.

  • Binding of glucose to phosphorylase enzyme (responsible for glycogen mobilization) causes a conformational change.

  • This conformational change enables phosphorylase A phosphatase to bind and inactivate the phosphorylase enzyme.

  • Insulin stimulates glycogen synthesis while inhibiting glycogen breakdown or mobilization.

Insulin's Effect on Glycolysis and Gluconeogenesis

• Reactions in red refer to glycolytic reactions, while reactions in blue refer to gluconeogenesis.

• While the two processes are the reversal of each other, not all the steps are identical.

• Insulin stimulates hexokinase, which phosphorylates glucose.

• Insulin also stimulates phosphofructokinase, committing glucose to glycolysis and ensuring pyruvate formation.

  • Insulin ensures that phosphofructokinase is active while inhibiting gluconeogenesis.

  • Reciprocal regulation occurs.

• Pyruvate formed from glycolysis can undergo further oxidation to form acetyl CoA catalyzed by pyruvate dehydrogenase.

• Pyruvate dehydrogenase is also stimulated by insulin.

• The presence of insulin will ensure that this glucose molecule undergoes oxidation to produce ATP.

Insulin's Effect on Fatty Acid Synthesis

• Insulin activates the enzyme acetyl CoA carboxylase, which stimulates the synthesis of malonyl CoA from acetyl CoA.

• In the presence of insulin, citrate (a marker of a high energy status of the cell) is channeled towards the synthesis of fatty acids.

Insulin's Effect on Fatty Acid Synthesis and Oxidation

• Insulin activates acetyl CoA carboxylase, which promotes the formation of fatty acids via malonyl CoA.

• Malonyl CoA inhibits the transporter that transports fatty acids into the mitochondria, leading to their oxidation.

• Insulin promotes fatty acid synthesis while inhibiting the oxidation of fatty acids.

Well-Fed State

• Insulin secretion is high, and the liver is awash with nutrients like glucose, amino acids, and fatty acids.

• Glucose is distributed to other tissues:

  • The liver distributes glucose to other tissues, checking to see whether all tissues have a good supply of glucose before it utilizes it for its own purposes.

  • The glucose is sent off in all different directions initially to the brain, because the brain can use only glucose as a source of energy aside from ketone bodies.

  • Transported to the brain, muscle, adipose tissue, nervous system, red blood cells, and so on.

• Excess glucose is converted to glycogen.

• Glucose can also be oxidized to form energy:

  • Glucose is oxidized to pyruvate, which is then oxidized to acetyl CoA.

  • Acetyl CoA can be further oxidized to produce carbon dioxide and water, coupled with ATP synthesis.

  • Acetyl CoA can also be a building block for triacylglycerol synthesis.

• Triacylglycerol synthesized in the liver is transported via lipoproteins to other tissues.

• Fats in the diet are absorbed as chylomicrons:

  • Triacylglycerol in chylomicrons is brought to the liver via the lymphatic system and contributes to the liver pool of triacylglycerol.

  • Triacylglycerol is transported to various other tissues in the form of lipoproteins.

  • Fatty acids or fats are brought to the muscle and used for energy.

  • The liver primarily focuses on creating storage molecules, predominantly in the form of triacylglycerol the lipogenic liver.

• Amino acids:

  • Amino acids in the diet are absorbed and brought to the liver via the blood.

  • In the liver, they undergo catabolism.

  • The amino group is separated from the carbon skeleton during breakdown.

  • The amino group is channeled towards ammonia formation, which is then excreted in the form of urea.

  • The carbon skeleton can be used for various biosynthetic processes.

Glucagon

• Once the blood glucose levels in the body drops, glucagon is stimulated.

• Glucagon works to raise blood glucose levels by synthesizing glucose or mobilizing glucose stores.

• Produced in the pancreas by the islets of Langerhans.

• In the liver:

  • Activates glycogen phosphorylase, the enzyme responsible for glycogen mobilization.

  • Inactivates the enzyme responsible for glycogen synthesis.

  • Inhibits glycolysis and stimulates gluconeogenesis.

  • Inhibits the glycolytic enzyme pyruvate kinase, favoring gluconeogenesis.

• In adipose tissue:

  • Activates triacylglycerol mobilization by activating the hormone-sensitive lipase.

  • This leads to the formation of free fatty acids and glycerol.

  • Free fatty acids are transported to other tissues, sparing glucose for the brain.

Fasting State

• The drive at this point of fast is for the liver to synthesize glucose.

• All the processes occurring lead to the formation of glucose, and that is why the liver is now described as the glucogenic liver.