Y1S2 006 I Biochem Glycolysis, Fat Oxidation, and Ketogenesis

Metabolic Paths

• Three metabolic paths: Glycolysis, Fat Oxidation, and Ketogenesis

Glycolysis

• Epinephrine binds to its receptor, activating adenylate cyclase, leading to phosphorylation of hormone-sensitive lipase
• This releases fatty acids from triacylglycerols, diacylglycerols, and monoacylglycerols through the action of monoacylglycerol lipase

Fat Oxidation

• Epinephrine binds to its receptor, activating adenylate cyclase, leading to phosphorylation of hormone-sensitive lipase
• This releases fatty acids from triacylglycerols, diacylglycerols, and monoacylglycerols through the action of monoacylglycerol lipase

Ketogenesis

• During high rates of fatty acid oxidation, acetyl-CoA is generated in excess of the TCA cycle's capacity
• This leads to the synthesis of Ketone Bodies (Acetoacetate, β-hydroxybutyrate, and acetone)
• Ketone Bodies are formed in Liver Mitochondria
• Acetoacetate and β-hydroxybutyrate are formed from acetyl-CoA in the liver mitochondria

Formation of Ketone Bodies

• Ketogenesis begins with the condensation of two acetyl-CoA molecules to form acetoacetyl-CoA
• Acetoacetyl-CoA and an additional acetyl-CoA are converted to β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) by HMG-CoA synthase
• HMG-CoA is then cleaved into acetoacetate and acetyl-CoA

β-Hydroxybutyrate Dehydrogenase

• Catalyzes interconversion of the ketone bodies acetoacetate and β-hydroxybutyrate
• The first step involves the reversal of the β-hydroxybutyrate dehydrogenase reaction
• The second step involves the action on acetoacetate by succinyl-CoA transferase (also called ketoacyl-CoA-transferase)

Regulation of Ketogenesis

• Control of free fatty acid release from adipose tissue directly affects the level of ketogenesis in the liver
• The liver has sufficient supplies of glycerol-3-phosphate, most of the fats will be turned to the production of triacylglycerols
• Acetyl-CoA can be completely oxidized in the TCA cycle if the demand for ATP is high
• The level of fat oxidation is regulated hormonally through phosphorylation of ACC, which can activate or inhibit it

Acetone Formation

• Acetoacetate can undergo enzymatic conversion to β-hydroxybutyrate through the action of β-hydroxybutyrate dehydrogenase or spontaneous decarboxylation to acetone

Increased Release of Ketones

• 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, leading to increased release of ketone bodies from the liver

Utilization of Ketone Bodies

• Ketone bodies are utilized by extrahepatic tissues through the conversion of β-hydroxybutyrate to acetoacetate and of acetoacetate to acetoacetyl-CoA
• Heart and skeletal muscle will consume primarily Ketone Bodies to preserve glucose for use by the brain during early stages of starvation

Diabetic Ketoacidosis

• The most significant disruption in the level of ketosis occurs in untreated insulin-dependent diabetes mellitus
• This leads to diabetic ketoacidosis (DKA), resulting from a reduced supply of glucose and a concomitant increase in fatty acid oxidation
• 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 occurs due to the increase in ketone bodies, which can impair the ability of hemoglobin to bind oxygen