Ketone Body Metabolism And Disorders Flashcards
Explain Zellweger syndrome
Very long chain fatty acids (22 to 26 C atoms) oxidized in peroxisomes
– Shortened fatty acid next sent to mitochondria
• Zellweger syndrome: Defective peroxisomal
biogenesis (liver and brain)
• Increased C-26 fatty acids
• Neurological manifestations (delayed
development) and extensive demyelination
- Hepatomegaly and hepatocellular failure
- Usually fatal in infancy
Describe the alpha oxidation of branched chain fatty acids to Refsum disease)
• Phytanic acid (branched chain fatty acid) in dairy
products
• a-oxidation takes place in peroxisomes
• Refsum disease: Peroxisomal phytanyl CoA - hydroxylase deficiency (-oxidation defect)
– Phytanate accumulates
– Visual defects, ataxia and polyneuropathy and skeletal
manifestations
– Restrict branched chain fatty acids (phytanic acid)
What is omega oxidation?
• Minor pathway for fatty acid
oxidation in ER
• Oxidation of -C atom of fatty
acid, forms dicarboxylic acid
• When a-oxidation is defective (eg: MCAD deficiency), dicarboxylic acids found in urine
How are ketone bodies formed?
• Acetyl CoA from fatty acid oxidation used to form ketone bodies in
liver (peripheral tissues cannot synthesize ketone bodies)
• Acetoacetate, 3-hydroxybutyrate (-hydroxybutyrate) and
acetone
- Acetoacetate and 3-hydroxybutyrate transported to peripheral tissues
- Acetoacetate and 3-hydroxybutyrate weak acids (give off protons)
- In peripheral tissues reconverted to acetyl CoA→ TCA cycle
Summarize ketogenesis
• Liver mitochondria
• Mitochondrial HMG CoA synthase – Rate limiting enzyme of
ketogenesis (Differentiate from HMG CoA synthase of cholesterol synthesis)
- Spontaneous (non-enzymatic) decarboxylation of acetoacetate forms acetone (volatile, non-metabolizable compound). Acetone lost via lungs
- 3-hydroxybutyrate formed when increased NADH/NAD+ (Active -oxidation)
- During fasting (ketosis), major ketone body 3-hydroxybutyrate
Describe the utilization of ketone bodies
- Ketone bodies are formed in liver
- Used by peripheral tissues (skeletal and cardiac muscle, brain)
- Alternate fuel for brain (prolonged fasting)
- 3-hydroxybutyrate oxidized to acetoacetate
- Succinyl CoA:acetoacetate CoA transferase (thiophorase)
- Acetoacetyl CoA → Acetyl CoA → TCA cycl
Describe the mechanism of ketosis in starvation
- Decreasedinsulin/glucagonratio
- Hormonesensitivelipase(phosphorylated)active
- Increasedadiposetissuelipolysis
- Increased free fatty acids in circulation (1)
- Increased B-oxidation in liver (CPT-I active; Low Malonyl CoA) (2)
- B-oxidation increases NADH/ NAD+ and increases ATP levels (3)
- IncreasedacetylCoAandincreasedketogenesis
- Acetyl CoA activates pyruvate carboxylase (gluconeogenesis)
- Pyruvate is shunted to gluconeogenesis
- Oxaloacetate for gluconeogenesis rather than Krebs cycle (4)
- Acetyl CoA towards ketogenesis rather than Krebs cycle (5)
What is ketosis?
Ketone body prpduction > use of keyone bodies by peripheral tissues
What is the significance of ketoacidosis in starvation?
- Ketoacidosis is complication in prolonged starvation
- Weak acids buffered by bicarbonate; pH decreases
- Fatty acids NOT a fuel for brain even during starvation
- Ketone bodies used by brain during starvation–Spares muscle protein breakdown (amino acids) for gluconeogenesis – ‘Protein sparing effect of ketone bodies’
- Remember: -oxidation provides energy and acetyl CoA to activate gluconeogenesis. BUT, C atoms of acetyl CoA (Fatty acids) NOT directly used as precursors of gluconeogenesis.
Explain when ketoacidosis occurs in uncontrolled diabetes mellitus
- Mechanism of ketogenesis in type 1 diabetic is similar to starvation
- Uncontrolled diabetes mellitus, excessive adipose tissue lipolysis (very low insulin levels) Hormone sensitive lipase very active
- Ketogenesis by liver is more than ketone body utilization by peripheral tissues → very high ketone bodies levels (ketonemia)
- Ketone bodies lost in urine (ketonuria) – detected by dipstick
- Weak acids and tend to lose protons
- Protons buffered by HCO3-, serum HCO3- levels fall, causing severe acidosis (metabolic acidosis)
- High anion gap metabolic acidosis (Ketone bodies are unmeasured anions)
Describe kow hypoketonemia occurs in systemic fattyvacid oxidation disorders
Defect in -oxidation, results in hypoketonemia
- During fasting, in MCAD deficiency, decreased insulin/ glucagon ratio
- Activation of hormone-sensitive lipase and increased lipolysis in adipose tissue
- Increased free fatty acid levels
- Free fatty acid uptake increases, but, in MCAD deficiency, -oxidation defective
- Low rates of -oxidation, impaired gluconeogenesis → severe hypoglycemia
- Low -oxidation → Acetyl CoA NOT formed
- Liver ketogenesis impaired → hypoketonemia
- Hypoketonemia also in systemic carnitine deficiency, systemic CPT-I deficiency and Jamaican vomiting sickness (Systemic fatty acid oxidation disorders)
How does ketoacidosis occur in uncontrolled diabetes mellitus?
- Elevated 3-hydroxybutyrate and acetoacetate levels in blood and urine
- Acetone production increased
- “Fruity odor” of breath (Loss of volatile acetone)
- Increased rate and depth of respiration –hyperventilation (decreases PCO2), compensatory response in metabolic acidosis
- Why is ketoacidosis more common in type-1 diabetes but not so common in type-2 diabetics??
- Differentiate between ketoacidosis in prolonged starvation and ketoacidosis in type-1 diabetic?
What are the ketogenic diets?
• High fat, low carbohydrate diets (Atkins diet) induce
ketosis – weight loss diets
• Less than 130g/day carbohydrate results in ketosis
(Ketogenic diets have 20-40g carbs)
- Low carbohydrate diets are ketogenic
- Management of refractory epilepsy
- Ketogenic diet: Fatty foods such as butter, cream, and peanut butter.
- Limit:Bread,pasta,fruits,andvegetable
What are the characteristics of hormone sensitive lipase?
- Location: Within adipocytes
- Role of insulin: Inhibits HS lipase
- Action: Breaks down storage TAG in adipose tissue to free fatty acids and glycerol
• Increased activity of HS lipase: – Starvation
– Insulin resistance (high circulating free fatty acid levels)
– Uncontrolled type 1 diabetes mellitu
What are the characteristics of lipoprotein lipase?
- Location: Endothelium of blood vessels in adipose tissue and muscle
- Role of insulin: Induces lipoprotein lipase and required for optimum activity
- Action: Breaks down TAG in chylomicrons and VLDL to free fatty acids that enter adipocytes to be converted to TAG for storage within adipocytes
- Decreased activity of lipoprotein lipase: Metabolic syndrome and Type II diabetes mellitus → Increased serum TAG (VLDL) → increases risk for cardiovascular disease (macrovascular complications
