NUTR 470 1st Edition Lecture 17-Nutritional Regulation of Ketogenesis-Ketogenesis• Definition: Ketogenesis is the process by which ketone bodies are produced as a result of fatty acid oxidation.• Location: Ketone bodies are produced in mitochondria of liver cells.•--Ketone Bodies• Types of ketone bodies-Acetoacetate-Acetone-β-hydroxybutyrate • Each of these metabolites is synthesized from acetyl-CoA molecules.-Ketogenesis• The formation of acetoacetyl-CoA• The formation of 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA)--Ketogenesis• The formation of 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA)-3-hydroxy-3-methyl glutaryl-CoA (HMGCoA) synthase is the key enzyme whose activationenhances ketogenesis.-HMG-CoA synthase is present in large amounts only in the liver.• The split of HMG-CoA-In the mitochondria, HMG-CoA lyase is the enzyme that causes acetyl-CoA to split off from the HMG-CoA, leaving free acetoacetate. -Interrelationships of the Ketone Bodies• Generation of acetone-Acetoacetate undergoes spontaneous decarboxylation to yield acetone.• Generation of 3-hydroxybutyrateThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.-Acetoacetate and 3-hydroxybutyrate are interconverted by the mitochondrial enzyme 3 hydroxybutyrate dehydrogenase.-Regulation of Ketogenesis• Ketogenesis is regulated at three crucial steps.• Step 1: Regulation of FFA mobilization-Free fatty acids are the precursors of ketone bodies in the liver. -Factors regulating FFA mobilization from adipose tissue are important in controlling ketogenesis.• Step 2: Regulation of fatty acid oxidation-After uptake by the liver, FFA is either oxidized to CO2 or ketone bodies or esterified to trigerlycerides or phospholipids.-CPT1 controls the entrance of FFA to mitochondria for oxidation.• Step 3: Generation of acetyl-CoA-Acetyl-CoA can be completely oxidized in the TCA cycle, or enters the pathway for ketogenesis. -As the levels of fatty acids are high, proportionately more acetyl-CoA is converted to ketone bodies.--Regulation of Ketogenesis• Nutritional and hormonal signals are responsible for the regulation of ketogenesis. • Availability of glucose-When glucose is in excess, some glucose is fully metabolized, and some of it is stored by using acetyl-CoA to create fatty acids (through lipogenesis).-When glucose is not enough, oxidation of fatty acid generates acetyl-CoA, which is not being recycled through the TCA cycle-The resulting accumulation of acetyl-CoA increases ketogenesis.-Under fasted conditions, glucagon appears to favor ketogenesis.-Hormonal—Under fed conditions, insulin appears to suppress ketogenesis.-Significance of Ketogenesis• When glucose is not enough-Fatty acid oxidation is favored, which in turn brings about an increase in ketogenesis.-Ketone bodies are fuel for extra hepatic tissues-The heart and skeletal muscles use ketone bodies for energy, thereby saving the limited glucose for the use by the brain.-The brain depends on ketone bodies as the fuel under starvations.-Clinical Aspects— Ketosis• Higher than normal quantities of ketone bodies present in the blood or urine lead to ketonemia or ketonuria, respectively.• Ketoacidosis results from prolonged ketosis.• The overall condition is termed as ketosis.• Acetoacetate and 3-hydroxybutyrate are both moderately strong acids – ketoacidosis may be fatal. -Summary-Reactions of ketogenesis-Significance-Regulation of ketogenesis-Ketogenesis and ketone