Ketogenesis: metabolic pathways PDF

Metabolic Paths 1. Glycolysis 2. Fat Oxidation 3 Ketogenesis Overview of General Metabolism Lecture 3 1. Recap of Beta oxidation 2. Ketogenesis 1. Glycolysis Epinephrine binds its' receptor and activates adenylate cyclase. The increase in cAMP activates PKA which then phosphorylates hormone-sensitiv...

Metabolic Paths 1. Glycolysis 2. Fat Oxidation 3 Ketogenesis Overview of General Metabolism Lecture 3 1. Recap of Beta oxidation 2. Ketogenesis 1. Glycolysis Epinephrine binds its' receptor and activates adenylate cyclase. The increase in cAMP activates PKA which then phosphorylates hormone-sensitive lipase. This hydrolyzes FA from triacylglycerols and diacylglycerols. Finally FA is released from monoacylglycerols through the action of monoacylglycerol lipase 2. Fatty Acid Oxidation Epinephrine binds its' receptor and activates adenylate cyclase. The increase in cAMP activates PKA which then phosphorylates hormonesensitive lipase. This hydrolyzes FA from triacylglycerols and diacylglycerols. Finally FA is released from monoacylglycerols through the action of monoacylglycerol lipase β_ Oxidation 3. Formation of Ketone Bodies or Ketogenesis Ketogenesis During high rates of fatty acid oxidation, primarily in the liver, large amounts of acetyl-CoA are generated. These exceed the capacity of the TCA cycle, and one result is the synthesis of Ketone Bodies, or Ketogenesis. The term Ketone Bodies refers to three biosynthetically related products Acetoacetate, βhydroxybutyrate and acetone. Ketone Bodies are formed in Liver Mitochondria Acetoacetate and β-hydroxylbutyrate are formed from acetyl-CoA in the liver mitochondria. The liver releases the Ketone Bodies into the blood for transport to other tissues where they are used as an important source of metabolic energy. Small amount of acetone is formed by nonenzymatic de-carboxylation of acetoacetate. It has no recognizable biological function and most is exhaled through the lungs. During fasting or carbohydrate starvation, oxaloacetate is depleted in liver because it is used for gluconeogenesis. This impedes entry of acetyl-CoA into Krebs cycle. Acetyl-CoA then is converted in liver mitochondria to ketone bodies, Ketogenesis begins with the condensation of two acetyl-CoA molecules to form acetoacetyl-CoA: Acetoacetyl-CoA 1 + 1 Acetyl CoA molecules Condensation of another acetyl-CoA molecule yields 3hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) Formation of Acetoacetyl-CoA The formation of acetoacetyl-CoA occurs by condensation of two moles of acetylCoA through a reversal of the thiolase catalyzed reaction of fat oxidation. Acetoacetyl-CoA and an additional acetylCoA are converted to β-hydroxy-βmethylglutaryl-CoA (HMG-CoA) by HMGCoA synthase, an enzyme found in large amounts only in the liver. HMG-CoA is afterwards cleaved into acetoacetate and acetyl-CoA: Diagram of Steps in Ketones Formation β-Hydroxybutyrate Dehydrogenase catalyzes interconversion of the ketone bodies acetoacetate and β -hydroxybutyrate. Acetone Formation Acetoacetate can undergo enzymatically convertion to β-hydroxybutyrate through the action of β-hydroxybutyrate dehydrogenase or spontaneous decarboxylation to acetone Co2 H+ ← Spontaneous Acetone Acetyl CoA Formation Acetoacetate moves into the bloodstream and gets distributed to the tissues. Once absorbed, it reacts (in mitochondria) with succinyl-CoA, yielding succinate and acetoacetyl-CoA, which can be cleaved by thiolase into two molecules of acetyl-CoA. Increased Release of Ketones From The Liver When the level of glucagon is high the production of β-hydroxybutyrate increases. When carbohydrate utilization is low or deficient, the level of oxaloacetate will also be low, resulting in a reduced flux through the TCA cycle. This in turn leads to increased release of ketone bodies from the liver for use as fuel by other tissues. Using Ketones : Preserving Glucose In early stages of starvation, when the last remnants of fat are oxidized, heart and skeletal muscle will consume primarily Ketone Bodies to preserve glucose for use by the brain. Acetoacetate and β-hydroxybutyrate, in particular, also serve as major substrates for the biosynthesis of neonatal cerebral lipids. Extrahepatic Tissues Utilization of Ketone Bodies Ketone bodies are utilized by extrahepatic tissues through the conversion of βhydroxybutyrate to acetoacetate and of acetoacetate to acetoacetyl-CoA. The first step involves the reversal of the βhydroxybutyrate dehydrogenase reaction, and the second involves the action on acetoacetate by succinyl-CoA transferase, also called ketoacyl-CoA-transferase. Ketoacyl-CoA-Transferase. This enzyme is present in all tissues except the liver. Importantly, its absence allows the liver to produce Ketone Bodies but not to utilize them. This ensures that extra-hepatic tissues have access to Ketone Bodies as a fuel source during prolonged fasting and starvation. Regulation of Ketogenesis Control in the release of free fatty acids from adipose tissue directly affects the level of ketogenesis in the liver. This is, of course, substrate-level regulation. Once fats enter the liver, they have two distinct fates. They may be activated to acyl-CoAs and be oxidized, or esterified to glycerol in the production of triacylglycerols. If the liver has sufficient supplies of glycerol-3phosphate, most of the fats will be turned to the production of triacylglycerols. Acetyl-CoA by oxidation of fats can be completely oxidized in the TCA cycle. Therefore, if the demand for ATP is high the fate of acetyl-CoA is likely to be further oxidation to CO2. The level of fat oxidation is regulated hormonally through phosphorylation of ACC, which may activate it (in response to glucagon) or inhibit it (in the case of insulin). Untreated Type1 Diabetes (Insulin Dependent) The most significant disruption in the level of ketosis, leading to profound clinical manifestations occurs in untreated insulindependent diabetes mellitus. This physiological state, diabetic ketoacidosis (DKA), results from a reduced supply of glucose (due to a significant decline in circulating insulin) and a concomitant increase in fatty acid oxidation (due to a concomitant increase in circulating glucagon). The increased production of acetyl-CoA leads to ketone body production that exceeds the ability of peripheral tissues to oxidize them. Acidification of the Blood Ketone Bodies are relatively strong acids (pKa around 3.5), and their increase lowers the pH of the blood. This acidification of the blood is dangerous chiefly because it impairs the ability of hemoglobin to bind oxygen. Ketoacidosis in Diabetes Ketocidosis means dangerously high levels of ketones. Ketones poison the body. Ketones in urine are a warning sign that your diabetes is out of control or that you are very sick. Ketoacidosis usually develops progressively. Signs of Diabetic Ketoacidosis Elevated glucose level Dry or flushed skin vomiting, nausea and abdominal pain. Breathing difficulties Fruity odor of breath Confusion Summary During healthy regular life, glucose breakdown provides energy During exercise mobilization of fatty acids and breakdown give the body energy from fat stores 3. During diabetes mellitus, Ketogenesis leads to diabetic ketoacidosis