BIOQUI - 06/07/2023

Introduction to Ketogenesis

Overview of Ketogenesis

• The lecture begins with an introduction to ketogenesis, defined as the formation of ketone bodies.

• Ketone bodies are negatively charged compounds produced exclusively in the mitochondria of the liver from excess acetyl-CoA derived from fatty acids during high lipolysis.

Mechanism of Ketone Body Formation

• Fatty acids from adipose tissue and dietary sources undergo beta-oxidation in the liver, generating acetyl-CoA which can either enter the Krebs cycle or be converted into ketone bodies.

• Excessive production of acetyl-CoA leads to a condition known as ketoacidosis due to increased hydrogen ions associated with negatively charged ketone bodies.

Energy Production and Utilization

• Ketone bodies serve as energy sources, particularly for the brain during fasting states when beta-oxidation is elevated.

• The three primary ketone bodies are acetoacetate, beta-hydroxybutyrate, and acetone; their synthesis occurs when blood sugar levels are low.

Physiological Context of Ketogenesis

Conditions Leading to Increased Ketogenesis

• Diabetic patients, especially those with type 1 diabetes, may experience ketoacidosis due to prolonged fasting or insufficient insulin leading to mobilization of energy stores.

• Acetone is expelled through respiration while other ketones are transported to peripheral tissues where they convert back into acetyl-CoA for energy production.

Importance in Metabolism

• The process occurs primarily in mitochondria and is triggered by excessive fatty acid breakdown (lipolysis), resulting in high levels of acetyl-CoA.

Biochemical Pathway Involved in Lipid Metabolism

Lipolysis and Fatty Acid Activation

• Lipolysis releases free fatty acids from triglycerides stored in adipose tissue; these fatty acids then circulate in the bloodstream bound to albumin before reaching the liver.

• Once at the liver, free fatty acids are activated into acyl-CoA derivatives before entering mitochondria via carnitine transport systems.

Beta-Oxidation Process

• Inside mitochondria, fatty acids undergo beta-oxidation facilitated by specific enzymes that convert them into acetyl-CoA molecules for further metabolic processes.

Final Steps: From Acetyl-CoA to Ketones

Conversion Process

• A significant portion of generated acetyl-CoA enters the Krebs cycle for ATP production; however, some is diverted towards forming ketones through a series of enzymatic reactions involving thiolase.

Summary of Key Points

HMG-CoA and Ketone Body Formation

HMG-CoA Synthesis

• The enzyme Hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase) removes coenzyme A through acetyl-CoA, forming a long compound known as HMG-CoA.

• HMG-CoA is crucial as it shares similarities with cholesterol synthesis; it forms from two acetyl-CoAs combining to create acetoacetyl-CoA.

Ketone Body Production

• An enzyme called HMG-CoA lyase removes an acetyl group from HMG-CoA, resulting in acetoacetate and releasing one acetyl group.

• Acetoacetate can spontaneously decarboxylate into acetone, which is another ketone body that is expelled via the lungs.

Key Ketone Bodies

• The primary ketone bodies formed are acetoacetate and beta-hydroxybutyrate. Acetoacetate converts to beta-hydroxybutyrate through the action of hydroxymethylbutyric acid dehydrogenase.

• Acetone is produced spontaneously from acetoacetate and eliminated by the lungs, while beta-hydroxybutyrate circulates in the blood.

Energy Source and Metabolism

• Acetoacetate and beta-hydroxybutyrate serve as significant energy sources during ketosis, promoting metabolic processes like ketoacidosis.

• These ketones diffuse into tissues such as liver, heart, kidneys, and brain for reactivation or catabolism back into acetyl-CoA.

Conversion Back to Acetyl CoA

• In peripheral tissues, ketones undergo a process called ketolysis where they convert back to acetyl CoA for energy production.

• The most abundant ketone entering extrahepatic tissues is beta-hydroxybutyrate; it converts back to acetoacetate via a reversible reaction facilitated by dehydrogenases.

Final Steps in Energy Production

• Enzymes involved include transferases that help convert acetoacetyl CoA back into two molecules of acetyl CoA for entry into the citric acid cycle.

Energy Metabolism: Ketogenesis and Fatty Acid Oxidation

Overview of Ketogenesis

• The importance of ketone bodies as a significant energy source is introduced, highlighting their role in metabolism.

• Free fatty acids circulate in the blood and are transported to the liver, where they are activated into acyl-CoA by coenzymes and specific enzymes.

Mechanism of Fatty Acid Entry into Mitochondria

• Activated fatty acids enter mitochondria through a transport system involving carnitine palmitoyl transferase I, which regulates their entry based on availability.

• Fatty acids that cannot enter mitochondria are esterified into glycerol esters and transported via very low-density lipoproteins (VLDL) to various tissues like muscle and brain.

Regulation of Lipogenesis

• Active fatty acids negatively regulate lipogenesis, primarily mediated by acetyl-CoA carboxylase, the key enzyme in this process.

• Insulin inhibits acetyl-CoA carboxylase while glucagon also plays a role in its inhibition; when active, it converts acetyl-CoA to malonyl-CoA.

Role of Malonyl-CoA in Metabolism

• Malonyl-CoA regulates carnitine palmitoyl transferase I's activity, determining whether fatty acids will be directed towards oxidation or lipogenesis.

• Insulin positively influences the conversion of acetyl-CoA to malonyl-CoA, leading to fatty acid synthesis.

Energy Yield from Ketone Bodies

• Ketogenesis is regulated by several factors including enzyme activity; ketone bodies generated provide energy for tissues during fasting or hypoglycemia.

• Acetoacetate generates 19 moles of ATP while β-hydroxybutyrate yields 21.5 moles; these values indicate their substantial energy contribution compared to glucose.

Clinical Implications of Fatty Acid Oxidation Disorders

• Rare metabolic disorders related to fatty acid oxidation can lead to hypoglycemia due to deficiencies in enzymes involved in these pathways.

• Conditions such as carnitine deficiency result in persistent hypoglycemia; other disorders affect hepatic function or skeletal muscle metabolism.

Diagnostic Approaches for Metabolic Disorders

• Diagnosis often involves liver biopsies and radioimmunoassays to detect enzyme deficiencies linked with ketogenesis errors.

• Commonly diagnosed conditions include hydroxymethylglutaryl-coenzyme A lyase deficiency, which requires advanced technology for accurate identification.

Conclusion on Metabolic Pathways

• Understanding these metabolic pathways is crucial for diagnosing rare diseases associated with ketogenesis and fatty acid oxidation disorders.

Cetoacidosis Alcohólica y Diabética

Mecanismos de Cetoacidosis Alcohólica

• La cetoacidosis alcohólica se produce por el abuso del alcohol, que altera la gluconeogénesis, un proceso clave en la formación de azúcar a partir de compuestos no carbohidratados.

• El alcohol interfiere con la gluconeogénesis, resultando en hipoglicemia en pacientes alcohólicos debido a la falta de producción de glucosa nueva en el hígado.

• La hipoglicemia provoca cambios hormonales significativos: disminución de insulina y aumento de hormonas como glucagón, cortisol y adrenalina, lo que favorece la liberación de ácidos grasos libres.

• Los pacientes alcohólicos tienden a ser delgados porque queman grasas para liberar ácidos grasos libres al plasma debido a la hipoglicemia provocada por el alcohol.

• Los altos niveles de glucagón y ácidos grasos libres promueven su oxidación, generando acetil-CoA que forma cuerpos cetónicos, caracterizando así la cetoacidosis alcohólica.

Efectos Bioquímicos del Alcohol

• La conversión del acetato por acción del alcohol aumenta los niveles reducidos de NADH frente a NAD+, afectando procesos bioquímicos cruciales.

• Este desequilibrio eleva los niveles de acetoacetato y promueve una mayor cetosis debido a cambios estructurales en las mitocondrias inducidos por el alcohol.

• El exceso de NADH impide su utilización en procesos oxidativos mitocondriales, contribuyendo a una menor oxidación de ácidos grasos y formando compuestos tóxicos para varios tejidos.

Consecuencias Clínicas

• El etanol actúa como glicerol al captar ácidos grasos, creando un compuesto tóxico que afecta órganos como el páncreas y corazón, llevando a miocardiopatía alcohólica y pancreatitis.

• Los pacientes pueden experimentar síntomas como náuseas, vómitos y dolor abdominal. También son propensos a desnutrición crónica e inestabilidad hidroelectrolítica.

Complicaciones Asociadas

• Se presentan trastornos neurológicos como encefalopatía Wernicke debido a deficiencia vitamínica (tiamina), además de encefalopatía hepática por exceso de amonio intestinal.

Cetoacidosis Diabética

Características Generales

• La cetoacidosis diabética es una complicación metabólica específica asociada principalmente con diabetes tipo 1 pero también puede ocurrir raramente en tipo 2.

• Se origina por deficiencia absoluta o relativa de insulina amplificada por hormonas antiinsulinas (glucagón, catecolaminas).

Metabolismo Alterado

• En diabetes tipo 1 se bloquea el ciclo de Krebs; esto redirige el metabolismo hacia la formación excesiva de cuerpos cetónicos que ingresan al torrente sanguíneo.

• Esto resulta en acetonuria ya que los cuerpos cetónicos deben eliminarse por orina; si no se corrige adecuadamente puede ser mortal para el paciente.

Tratamiento Necesario

Understanding Diabetic Ketoacidosis and Pharmacological Interventions

The Mechanism of Diabetic Ketoacidosis

• Diabetic ketoacidosis (DKA) is linked to elevated ketone levels, which are highly toxic. This condition arises from the accumulation of circulating ketones in the body.

• A biochemical-pharmacological relationship exists regarding DKA, emphasizing the importance of understanding enzymes involved in its production and regulation.

Pharmacological Treatments for Diabetes

• Medications such as glibenclamide and tolbutamide are hypoglycemic agents that play a role in managing diabetes by reducing fatty acid oxidation.

• These medications inhibit carnitine palmitoyltransferase 1, an enzyme crucial for transporting fatty acids into mitochondria, thereby affecting energy metabolism.

Conclusion on Lipids and Diabetes Management

• The discussion on lipids will continue with another instructor after a break, highlighting the ongoing exploration of their role in diabetes management.