Fats II- Ketogenesis and Cholesterol Synthesis Flashcards
Before oxidation, what enzyme activates fatty acids and links them to coenzyme A?
Thiokinase enzyme
What is the process by which fats can be fully oxidised to ATP?
β-oxidation produces Acetyl Co-A
- Can be converted into ATP or ketone bodies
How are ketone bodies used for energy?
- Sent to bloodstream and travels to tissues NOT the liver
- Converted to Acetyl CoA
Where is the only place gluconeogenesis occurs?
Liver
- The only organ that can make glucose
What process provides fatty acids for oxidation and energy production?
Lipolysis
What substance may the body draw on for substrates of essential proteins and carbon for gluconeogenesis in a state of fasting and starvation?
Muscle protein
What are the useful products of β oxidation?
- Acetyl CoA
- FADH2 and NADH
What is driving ketogenesis during fasting/starvation?
- β-oxidation drives Acetyl CoA
- Intermediates originally provided by amino acid oxidation are removed from TCA cycle are used for gluconeogenesis
- Insufficient oxaloacetate to drive TCA cycle and use up acetyl CoA molecules from β-oxidation
- Excess Acetyl CoA accumulates which undergoes ketogenesis
What does the liver need to continue β-oxidation?
Free coenzyme A
Where is the only place that ketone body synthesis takes place?
Mitochondrial matrix
What are the three ketone bodies that acetyl CoA can be converted to?
- Acetoacetate
- β-hydroxybutyrate
- Acetone
What are ketone bodies converted to serve as an energy source?
- Acetyl CoA
Which ketone bodies are more common?
- Acetoacetate
- β-hydroxybutyrate
What happens to ketone bodies when they are not being used?
Acetone
What are the two key enzymes in ketogenesis from Acetyl CoA?
- HMG-CoA synthase
- HMG-CoA lyase
(unique to hepatocytes)
How is acetone excreted?
Via urine or lungs
What do two acetyl CoA molecules produce?
- Acetoacetyl CoA
- One co-enzyme A molecule is released and used in β-oxidation
What happens to acetoacetyl CoA after it is produced?
- Reacts with another acetyl CoA
- Produces HMG CoA (essential intermediate)
What enzyme catalyses the reaction between Acetoacetyl CoA and Acetyl CoA?
HMG CoA synthase
What is HMG CoA converted to in ketogenesis?
Acetoacetate
What enzyme catalyses the reaction converting HMG-CoA to acetoacetate?
HMG-CoA lyase
What is Acetoacetate converted to in ketogenesis and what enzyme catalyses this?
- β-hydroxybutyrate
- β-hydroxybutyrate dehydrogenase
- NADH + H+ -> NAD+
What is detectable on a diabetic’s breath as a sign that they are undergoing ketogenesis?
Acetone
- Both acetoacetate and β-hydroxybutyrate
Describe the fate of ketone bodies
- Synthesised in the liver
- Conversion back to Acetyl CoA
- Oxidation in the TCA cycle in other tissues
- Occurs in muscle and the brain during starvation
Briefly describe type 1 diabetes mellitus
- Elevated blood glucose results from inadequate secretion of insulin by islets of Langerhans in the pancreas
Briefly describe type 2 diabetes mellitus
- Shortage of insulin receptors- desensitisation to them
What happens to glucose transport in diabetes mellitus?
- Transport of glucose into muscle, liver and adipose tissue is significantly reduced
- Cells are metabolically starved
What happens to oxaloacetate in diabetes mellitus?
- Increased gluconeogenesis consumes most of the available oxaloacetate
What is an indication of high plasma levels of ketone bodies?
- Acetone detected on the breath of type 1 diabetics
What is the blood-brain barrier’s permeability to ketone bodies dependent on?
Monocarboxylic acid transporters (MCT-1)
What increases the number of MCT1 transporters in the blood-brain barrier?
- Fasting
How can we tell that the only essential role of ketone bodies is as an alternative fuel for illness/long-term fasting?
- Most patients with inborn errors involving ketogenesis develop normally
What does imaging show as a symptom of HMG-CoA lyase deficiency?
- Imaging generally shows asymptomatic white-matter abnormalities
In what case would a ketogenic diet be effective?
- In those who have a GLUT-1 deficiency
- Where a high glucose diet may not be useful
- Also successful treatment for patients with intractable epilepsy
Describe the ketogenic diet
- High in fat, moderate protein, low carbohydrate
- Treatment for those whose tissues cannot access or properly process carbohydrates (like in pyruvate dehydrogenase deficiency)
What is cholesterol?
A major class of lipid used in the body
What are the functions of cholesterol?
- Structural component of cell membranes- confers fluidity and regulates permeability
- Substrate for synthesis of sex hormone, vitamin D and bile acids
What is cholesterol mainly composed of?
- Carbon and hydrogen
- And solitary hydroxyl group attached to C3
- Almost completely saturate one double bond at C5=C6
- Mainly hydrophobic
Where is cholesterol synthesised?
- Liver is the main site
Where can cholesterol be obtained in the diet?
- Animal fat
What is the rate limiting regulatory enzyme for cholesterol biosynthesis?
- HMG- CoA reductase
What enzyme is cholesterol synthesis is a target of statins (drugs)?
HMG-CoA reductase
Describe the synthesis of cholesterol
- 2 Acetyl CoA produce AcetoacetylCoA
- CoA used in β-oxidation
- Acetoacetyl CoA converted to HMG-CoA using enzyme HMG-CoA synthase
- -CoA byproduct used in β-oxidation
- HMG-CoA converted to Mevalonate which is then converted to Lanosterol
- Both reactions use HMG-CoA reductase
- Lanosterol converted to cholesterols
What inhibits HMG-CoA reductase in a negative feedback loop?
- Cholesterol
What happens when statins inhibit HMG-CoA reductase?
- Lowers levels of endogenously synthesised cholesterol
- Stimulates increased LDL receptor expression in order to extract more cholesterol from blood
- Lowers plasma cholesterol and risk of MI
What do fungal cells convert lanosterol to?
- Ergosterol
What is ergosterol?
- Important component of fungal cell membranes and not animal cell
- Useful drug target
What are examples of anti-fungals that inhibit enzymes necessary for ergosterol generation?
- Terbinafine
- Imidazole
