BIOCD 1501 L30 Metabolic Regulation of Injury PDF

BIOCD 1501 Lecture 30 Dr. Thomas Bodenstine Metabolic Regulation of Injury Introduction In response to...

BIOCD 1501 Lecture 30 Dr. Thomas Bodenstine Metabolic Regulation of Injury Introduction In response to injury or infection, human metabolism changes in a myriad of ways. Healthy human metabolism is regulated in response to the availability of nutrition, and by insulin and glucagon; epinephrine facilitates the rapid mobilization of fuels to power a “flight or fight” response. These same endocrine hormones, in addition to cortisol and others, comprise the endocrine hormones that are involved in our response to injury and increase basal metabolic rate. Cortisol is considered a counter-regulatory hormone, meaning that it opposes the action of insulin. The release of cortisol in injury contributes to a hyper-metabolic state, in which catabolic processes are generally favored. Glucose levels increase due to increased gluconeogenesis. This mild hyperglycemia promotes glucose uptake and anaerobic metabolism in healing tissues. Breakdown of triacylglycerol also plays a major role in the support of human metabolism following injury. Skeletal muscle catabolism is a source of amino acids for a variety of metabolic needs, including as gluconeogenic substrates for liver. Amino acids are also needed in injury as substrates for protein biosynthesis in healing tissue and in the liver, which synthesizes a host of proteins in response to injury or infection. Terminal objective: To describe biochemical concepts of human metabolism in response to injury and infection Enabling objectives: 1. Compare and contrast the following hormones: glucagon, insulin, epinephrine, and cortisol. Be able to describe where each is synthesized, when it is secreted, how it acts on target tissue(s). 2. What is meant by a hypermetabolic state? Explain how BMR is affected by various conditions, including injury and starvation. 3. Describe how glucose metabolism changes in response to injury, and how a hyperglycemic state can be helpful to healing tissue. 4. Describe how triacylglycerol is utilized during the response to injury and the role of glycerol and fatty acids. 5. Describe how amino acids derived from skeletal muscle catabolism are used during the metabolic changes following injury/infection. 6. Describe how liver metabolism changes following injury. What proteins are synthesized in lesser amounts than normal? What proteins are synthesized in greater amounts than normal? How are these changes helpful in response to injury? 1. Overview Response to injury There are many components involved in the body’s response to injury which includes changes to cardiac output, blood pressure, body temperature, blood coagulation, electrolyte balance, etc. In this lecture we will be focusing specifically on the metabolic changes in response to injury. 1A) Hormones Counter-regulatory hormones: oppose the action of insulin on metabolism. These hormones modify sensitivity to insulin and decrease insulin signaling, promoting a temporary state of insulin-resistance. Glucagon Epinephrine (a catecholamine) Cortisol (a glucocorticoid) Hormone changes during injury: The balance between insulin and counter-regulatory hormones shifts in the direction of counter-regulatory hormones which increase as insulin decreases. The high levels of counter-regulatory hormones affect signaling pathways to override some of the typical effects of blood glucose on insulin regulation. The effects of insulin, glucagon and epinephrine on metabolism have been discussed in previous lectures. 1B) Cortisol is important in the response to injury. 1. Cortisol is a steroid hormone synthesized in the adrenal gland Effects are mediated by cortisol entering the target cell, binding to its receptor and affecting gene regulation. Time scale: relatively slow 2. Cortisol is generated under normal circumstances in variable amounts that cycle with our 24-hour circadian clock with levels increasing during sleep, peaking just before waking. 3. Cortisol is a “counter-regulatory hormone” because in general: Its actions oppose those of insulin (as will be discussed) It promotes catabolic processes (insulin is anabolic) 4. Exhibits immunosuppressive and anti-inflammatory effects. This helps to control immune responses. As a result, cortisol, or some of its synthetic derivatives (e.g. prednisone, dexamethasone) are used in certain situations for their anti-inflammatory and immunosuppressive abilities. NOTE: When given as a medication, cortisol is referred to as “hydrocortisone”. 2  Excess cortisol Most common cause: adrenal gland tumor (Cushing syndrome) Symptoms (can be instructive with regard to normal function of cortisol) Truncal obesity, characterized by excess adipose in abdomen, chest and face, but thin arms and legs. Insulin resistance can result in diabetes mellitus. Poor immune system function can lead to infection. Poor wound healing. Insufficient cortisol Most common cause: auto-immune disease of adrenal gland (Addison disease) Symptoms Hypoglycemia Decreased blood pressure Stress causes a drop in blood pressure potentially resulting in shock 2. Hypermetabolic State Injury causes a “hypermetabolic” state. Basal metabolic rate (BMR) increases in response to injury. The increase in BMR is proportional to the injury. What is a hypermetabolic state? Altered state of body metabolism, where BMR is increased. 2A) Basal Metabolic Rate (BMR): 1. Definitions: “energy required by an individual during physical, digestive, and emotional rest;” “the rate of energy utilization in the resting state” 2. What normally determines our BMR? Body surface area: the greater the surface area, the greater the rate of heat loss. Age: Infants and children need more energy per unit of mass than adults in order to grow. (Infants triple in weight by age 1 year; their BMR reflects this.) Activity levels: Regular exercise increases an individual’s BMR. 3. How does starvation effect our BMR? It decreases BMR up to 50%! 4. How does injury affect our BMR? Severe stress or trauma increases BMR. Fever increases BMR. There is a 12% increase in BMR for each 1oC rise in body temperature. Burns can increase BMR by as much 2-fold! Severe infections can increase BMR by 50%! 3 3. Metabolism During the Hypermetabolic State Inter-organ carbohydrate metabolism results in hyperglycemia. This is caused by an excess of counter-regulatory hormones. 3A) Carbohydrate metabolism Following an injury, blood glucose levels increase causing a state of hyperglycemia. This rise in glucose is utilized by: Cells involved in repair and clearance of pathogens: immune cells, fibroblasts, etc. These cells exhibit high levels of anaerobic metabolism and thus require a sufficient source of glucose. Glucose is therefore the primary fuel source of cells at the site of injury. Kidneys increase utilization of glucose following injury. Fuel for cells, tissues and organs with non-insulin dependent glucose uptake that continue to utilize glucose. Where does elevated blood glucose come from? 1. Liver gluconeogenesis Substrates used for gluconeogenesis Lactate & pyruvate (from anaerobic metabolism) Amino acids from skeletal muscle (more on this below) Glycerol from breakdown of triacylglycerol stores (more on this below) 2. Liver glycogen catabolism Breakdown of glycogen in the liver releases glucose to the blood These effects are produced by the rise in glucagon and epinephrine as discussed in previous lectures. Additionally, cortisol also stimulates liver gluconeogenesis and glycogen breakdown. Skeletal muscle glycogen Counter-regulatory hormones cause the breakdown of glycogen in skeletal muscle. Reminder: this glucose cannot be released to the blood but serves as an additional source of energy within skeletal muscle. Skeletal muscle and adipose tissue Reduce their uptake of glucose from the blood. Remember, insulin is necessary for glucose to be internalized by these two tissues. The state of insulin-resistance induced by counter- regulatory hormones keeps glucose from being internalized by skeletal muscle and adipose (non-vital organs) and helps to maintain the state of hyperglycemia so that glucose can be used by other cells/tissues (as described above) to maintain critical body functions and wound repair. 4 3B) Protein metabolism Inter-organ protein metabolism results in release of amino acids from skeletal muscle. This is proportional to the severity of injury. 1. Amino acids released from skeletal muscle are used in many ways: Substrates for gluconeogenesis – amino acids from skeletal muscle are used as a continual substrate for gluconeogenesis to maintain the hypermetabolic state (discussed above) The intestine requires glutamine as fuel. It is extremely important to maintain the integrity of the intestine at all times, especially during injury/infection. Protein synthesis in the liver Function of immune cells Cells involved in healing the wound 2. Location of skeletal muscle breakdown is non-specific This is why patients often experience weakness during recovery even if the muscle was not originally damaged. This effect can be lessened by nutritional support, including amino acids. Breakdown of muscle under these circumstances happens in skeletal muscle. Cardiac muscle for example is not broken down as this would not be compatible with survival. Skeletal muscle can therefore be thought of as an expendable form of amino acids that can be restored following injury. However, unlike glycogen (storage form of glucose) and triacylglycerol (storage form of fatty acids), skeletal muscle is not a designated storage form of amino acids. Therefore, its breakdown is catabolic and causes weakness and other complications – breakdown of a tissue vs. breakdown of an energy reserve within a tissue. 3C) Fatty acid metabolism The increase in counter-regulatory hormones induces the breakdown of triacylglycerol stores in adipose tissue leading to the release of fatty acids and glycerol. Glycerol enters the blood and it taken up as a substrate for gluconeogenesis by the liver. Fatty acids enter the blood and are used by tissues and organs, especially skeletal muscle, as a source of energy through β-oxidation. Fatty acids become a major source of energy in many tissues and organs during the response to injury. Reminder: the brain largely does not use fatty acids as energy and therefore still requires glucose (and can also use ketone bodies). 5 4. Protein Production in the Liver 4A) Acute phase proteins How does production of proteins by the liver change in response to injury/ trauma/infection? 1. The liver makes less of some proteins. Examples: Albumin - carrier of hydrophobic molecules Transferrin - carrier of iron 2. The liver makes more of other proteins. Particularly, acute phase proteins are produced in higher amounts in response to injury and infection. Examples include C-reactive protein: a multi-purpose protein we’ll discuss separately below. Serum amyloid A: recruits immune cells to sites of injury Haptoglobin: combines with potentially harmful substances, such as hemoglobin, that may be released during cell lysis and tissue damage Coagulation factors: to promote & regulate hemostasis. Lipopolysaccharide binding protein: binds to lipopolysaccharide found on the surface of gram-negative bacteria and stimulates immune cell responses Component C3: a protein involved in the complement system. 4B) Complement system “Complement” refers to a particular cascade of proteins that circulate in the blood and have immune regulatory and anti-pathogenic functions. Most of these proteins exist in an inactive form (zymogen) but can be activated in response to infection. Thus, complement is an anti- pathogen system circulating in the blood as a defense mechanism against infection. The complement proteins are labeled C1 through C9. The complement “cascade” can be initiated by antibody binding to pathogens or recognition of specific carbohydrate groups on the surface of pathogens. This leads to a series (cascade) of activation of the complement proteins that have the following effects: Recruit immune cells to site of infection Bind to pathogens (e.g. bacteria) and signal engulfment (phagocytosis) by cells of the immune system (e.g. macrophage) Form a pore complex in the membrane of the pathogen leading to its lysis (rupture). Q: Does it make sense that following injury, it is advantageous to increase levels of complement proteins? A: Yes. Injury increases vulnerability to pathogens. 6 4C) C-reactive protein Acute phase protein which increases in response to rising levels of cytokine production as a result of injury (or infection). Possesses multiple functions: Stimulates complement system Binds to pathogens and promotes phagocytosis Enhances chemotaxis (cell movement) of immune cells C-reactive protein Clinical significance: Eur. Bioinformatics Institute C-reactive protein is a non-specific marker of inflammation that can be increased as a result of numerous conditions (doesn’t explain cause or location of inflammation). Levels rise in response to injury and infection. Increased C-reactive protein is associated with increased risk of conditions such as diabetes and cardiovascular disease. 5. Biochemical Reponses to Injury and Clinical Support 5A) Healing tissues require good nutrition Fuel for synthesis of ATP Many enzymes require vitamins and minerals 5B) Minimizing protein catabolism Can prevent extreme muscle loss by supplying: Good nutritional support Some medications - Example: propranolol which inhibits the action of epinephrine and counteracts the hypermetabolic state associated with injury. This prevents excessive catabolism and loss of skeletal muscle. Supplying glucose helps reduce utilization of amino acids as a substrate for gluconeogenesis and can reduce skeletal muscle protein catabolism. Supplying amino acids provides building blocks necessary for repair of tissue, synthesis of liver proteins, etc., and also helps to reduce skeletal muscle breakdown. NOTE: None of these interventions can completely inhibit the catabolism of skeletal muscle following injury. This is due to the rise in counter-regulatory hormones and insulin-resistance that develops. The overall process is variable and depends on many factors such as severity of injury, care during recovery and nutritional support. 7 Study Questions 1. After injury or infection, the liver increases secretion of each of the following proteins except A) albumin. B) complement component C3. C) C-reactive protein D) haptoglobin. 2. Which of the following is required as the principal fuel for energy production in cells that are in the initial phases of repairing a wound? A) Amino acids B) Fatty acids C) Glucose D) Glutamine 3. Which of the following occurs after injury or during infection? A) Glucose uptake is increased in adipose tissue. B) Metabolism slows to conserve free energy. C) Skeletal muscle catabolism results in amino acid release. D) Reduced insulin secretion promotes hypoglycemia. 4. Which of the following statements concerning cortisol is correct? A) Cortisol is a small peptide hormone that is synthesized in pancreatic α-cells. B) Binding of cortisol to its receptor in the liver prevents development of insulin resistance during injury. C) Cortisol stimulates protein synthesis in skeletal muscle. D) Cortisol stimulates gluconeogenesis in the liver during injury. Answers: 1A, 2C, 3C, 4D 8