Principles of Medical Biology Lec. 4: Medical Biology in Cellular Metabolism

Medical Biology in Cellular Metabolism

Introduction to Metabolism

• Metabolism encompasses all chemical reactions within a living organism's cells.
• These reactions provide energy for vital processes and synthesize new organic material.
• Metabolism involves the metabolic rate and its effect on a healthy diet.

Metabolism: Anabolism vs. Catabolism

• Metabolism is the sum of catabolic and anabolic processes:
  • Metabolism = Catabolism + Anabolism
• Catabolism:
  • Breaks down complex molecules into simpler ones.
  • Releases energy.
  • Involves the breakdown of energy-yielding nutrients like carbohydrates, fats, and proteins.
  • Produces chemical energy in the form of ATP and NADH.
  • Generates waste products such as CO2, H2O, and NH_3.
• Anabolism:
  • Synthesizes macromolecules from smaller precursor molecules.
  • Requires energy.
  • Involves the synthesis of glycogen, lipids, proteins, nucleic acids, and polyamines.
  • Utilizes energy and nutrients like glucose, amino acids, and fatty acids for growth and energy storage.

Cellular Respiration

• Process:
  1. Digested nutrients are absorbed from the small intestine into the bloodstream.
  2. Nutrients are transported to cells via the bloodstream.
  3. Nutrients enter cells in various forms (fatty acids, glycerol, glucose, pyruvate, amino acids).
  4. Cellular respiration breaks down food to produce energy.
  5. The released energy is stored as ATP.
• Inputs: Fats, carbohydrates, and proteins are broken down into fatty acids, glycerol, glucose, pyruvate, and amino acids.
• Process location: Occurs in the mitochondrion.
• Outputs: Produces water (H2O), carbon dioxide (CO2), and ATP.

Interconversion of Metabolic Fuels

• Glucose and amino acids cannot be synthesized from fatty acids.

Carbohydrate Metabolism

• Carbohydrates are broken down in the mitochondria.
• Equation:
  • Glucose is converted into carbon dioxide and water.
  • The energy released is used to synthesize ATP.
• Glucose is produced from carbon dioxide and water via photosynthesis, using energy from the sun.
• All food ultimately comes from photosynthesis.
• Glycolysis:
  • 6-carbon glucose molecule is broken down into two 3-carbon pyruvate molecules.
  • Occurs in the cytoplasm.
  • Anaerobic (does not require oxygen).
• Aerobic reactions:
  • Pyruvate molecules move into the mitochondrial matrix.
  • Pyruvate is converted into water and carbon dioxide.
  • Carbon dioxide is removed from pyruvate.
  • Water is formed when oxygen combines with hydrogen from the original glucose molecule.
• Complex carbohydrates take longer to digest than simpler sugars due to more chemical bonds.
• Endurance athletes load up on complex carbohydrates to increase available energy during competition.

Electron Transport Chain

• Involves complexes I, II, III, and IV.
• NADH and FADH2 donate electrons.
• Ubiquinone (coenzyme Q) is involved.
• Protons are pumped into the cell.
• Electrons follow a specific path.
• Oxygen accepts electrons and combines with hydrogen to form water (H_2O).
• Cytochrome C and cytochrome B are involved.

Protein Metabolism

• Most protein is broken down into amino acids, which are then used to synthesize new proteins.
• Proteins can be broken down to supply energy when fat or carbohydrate is unavailable.
• In extreme starvation, the body breaks down muscle to produce ATP.
• Process:
  1. The nitrogen-containing amino group is removed from the amino acid.
  2. Amino groups are converted to urea, which is excreted in urine.
  3. The remaining carbon, oxygen, and hydrogen undergo further breakdown and enter the mitochondria to produce ATP.

Fat Metabolism

• Glycerol and fatty acids enter the mitochondria to produce ATP.
• Most cells break down fat when carbohydrate supplies are depleted.
• Excess Calories are converted into fat and stored for later use.
• Too much or too little body fat can cause health problems.

Metabolic Actions of Insulin

• Insulin is a major anabolic hormone secreted in response to carbohydrate- and/or protein-containing meals.
• Anabolic hormones promote protein synthesis, increasing lean body mass.
• Other anabolic hormones include thyroid hormones, growth hormone/IGF-I, and sex steroids (androgens).

Effects of Insulin on Carbohydrate Metabolism

• Increases glucose uptake and metabolism in muscle and fat.
• Increases glycogen synthesis in the liver and muscle by:
  • Increasing the activity of glycogen synthesis enzymes (glucokinase and glycogen synthetase).
  • Decreasing the activity of glycogen breakdown enzymes (phosphorylase and glucose-6-phosphatase).
• Glucokinase and glucose-6-phosphatase are expressed by the liver but not skeletal muscle.

Diabetes

• Disorder of carbohydrate metabolism characterized by impaired ability to produce or respond to insulin.
• Insulin is secreted by beta cells in the pancreas.
• Insulin triggers cells to take up glucose.
• People with diabetes cannot metabolize glucose, resulting in high blood glucose levels.
• Process in Non-Diabetic Person:
  1. High blood sugar following a meal.
  2. Pancreas secretes insulin into the bloodstream.
  3. Insulin triggers cells to take up glucose.
  4. Excess glucose is stored in the liver as glycogen.

Effects of Insulin on Protein Metabolism

• Increases amino acid uptake by muscle cells.
• Increases protein synthesis.
• Decreases protein breakdown; insulin deficiency results in protein breakdown.

Effects of Insulin on Fat Metabolism (Insulin Increases)

• Glucose uptake by fat cells via increased membrane transporters.
• Triose phosphates become available for triglyceride synthesis in adipose tissue.
• Triglyceride uptake by fat cells.
  • Increases the activity of lipoprotein lipase (extracellular lipase) which clears VLDL and chylomicrons from the blood.
• Triglyceride synthesis (lipogenesis) in adipose tissue and liver by stimulating the carboxylation of acetyl CoA to malonyl CoA.
  • Insulin stimulates the conversion of carbohydrate into fat.

Effects of Insulin on Fat Metabolism (Insulin Decreases)

• Triglyceride breakdown (lipolysis) in adipose tissue by decreasing the activity of hormone-sensitive lipase.
  • Hormone-sensitive lipase is activated by stress hormones (cortisol, growth hormone, epinephrine [glucagon]).
• Formation of ketone bodies by the liver.

Metabolic Effects in Insulin-Deficient Individuals

• Carbohydrate:
  • Increased blood glucose concentration.
  • Increased glycogen breakdown.
  • Decreased peripheral glucose use.
• Protein:
  • Increased protein breakdown.
  • Increased catabolism of amino acids.
  • Increased gluconeogenesis.
  • Increased ureagenesis.
  • Decreased protein synthesis.
• Fat:
  • Increased triglyceride breakdown.
  • Increased level of circulating free fatty acids.
  • Increased ketosis, resulting in ketoacidosis (metabolic acidosis).
  • Decreased fatty acid synthesis.
  • Decreased triglyceride synthesis.

Preferred Fuels in Well-Fed and Fasting States

Metabolic Rigidity and Metabolic Flexibility

• Adipocyte:
  • Energy Fuel: Glucose, O_2, Fatty-acids, triglycerides.
  • Energy Stores: Amino-acids, glycerol, fatty acids, O_2, Glycogen, Triglycerides
• Liver:
  • Glucose, pyruvate, fatty acids, triglycerides, amino acids, proteins, ketone bodies, lactate, O_2
• Skeletal Muscle:
  • Glucose, Glycerol, fatty acids, aminoacids, Ketones, O_2, Proteins
• Heart:
  • Glycerol, fatty acids, O_2
• Kidney:
  • glucose, aminoacids, Proteins
• Brain:
  • Glucose, O_2
  • Ketones

Metabolic Bone Disorders: Osteoporosis

• Osteoporosis is a loss of bone mass (both mineralization and matrix) with fractures, due to age-related changes and other factors.
• If bone mineral density is 2.5 standard deviations below the average, it equals osteoporosis.
• If bone mineral density is 1 to 2.5 standard deviations below the average, it equals osteopenia.
• Bone mass peaks after puberty.
• Heredity, physical activity, nutrition, and reproductive hormones (especially estrogens) play a significant role.
• Secondary osteoporosis can occur in thyrotoxicosis and with elevations in glucocorticoids.
• Treatment involves bisphosphonates, which reduce osteoclast activity and calcitonin to inhibit bone resorption.

Metabolic Bone Disorders: Rickets and Osteomalacia

• X-linked dominant.
• Symptoms include bone pain, skeletal abnormalities, bowed legs, and growth deficiencies.
• Origin is abnormal mineralization of bone and cartilage.
• Rickets occurs before plate closure, osteomalacia after plate closure.
• In rickets, there is expansion of the epiphyseal plates, bowing of the legs, and a protuberant abdomen.
• In osteomalacia, symptoms are more subtle.
• Common causes in adults include malabsorption disorders (e.g., celiac disease) and vitamin D deficiency.
• Rarely caused by enzyme deficiencies.

Cancer Metabolism

• Cancer cells consume glucose at a higher rate and produce more lactic acid than normal cells, even under aerobic conditions (Warburg effect).
• Increased ATP produced by glycolysis is used for fatty acid, protein, and DNA synthesis.
• The Warburg effect provides tumors with lactate and pyruvate, precursors to acetyl-CoA for fatty acid synthesis.
• Normal cells prefer to use OXPHOS in the mitochondria for energy, whereas tumor cells prefer aerobic glycolysis.

Cancer Metabolism: Abnormal Cancer Metabolism

• Genetic and epigenetic alterations occur, including:
  • Mutations in oncogenes, tumor suppressors, and enzymes.
• Increases in biosynthesis, including Proteins, Lipids, and Nucleic acids
  • Increase in Bioenergy and ATP production with Glycolysis dependence
• Leads to Altered Redox Balance
  • Increase Buffering Capacity
  • Increase Transporter Expression.
  • Leads to decrease in pH, in the Tumor Microenvironment.
• HIF-1 dynamically modulates local signaling pathways in hypoxic regions. Abnormal Cancer Metabolism