Chapter 16: Lipid Mobilization and Catabolism Flashcards
What hormones/neurotransmitters activate hormone sensitive lipase?
a decrease in : insulin
an increase in: cortisol and
epinephrine
MOA of niacin for combatting hyperlipidemia?
In large doses, it works by inhibiting HSL in adipose tissue.
With fewer FAs entering the liver, VLDL will not be assembled in normal amounts.
Both VLDL (carrying triglycerides and cholesterol) and its product, LDL, will lower in serum
Create of diagram for lipolysis of triglycerides in response to hypoglycemia and stress.
Refer to diagram.
What are the 2 organs which cannot oxidize FAs?
brain and erythrocytes
Why can the brain and erythrocytes not oxidize fatty acids?
The RBCs have no mitochondria and FAs do not cross the BBB efficiently.
Short chain fatty acids avg. number.
2-4 carbons
Medium chain fatty acids avg. number.
6-12 carbons
Long chain fatty acids avg. number.
14 -20 carbons
Describe the oxidation process for very long chain fatty acids?
enter peroxisome via an unknown mechanism for oxidation
Where is fatty acyl-CoA synthetase located in the cell?
on the outer mitochondrial membrane
Purpose of fatty acyl CoA synthetase?
activates the fatty acids by attaching CoA
How does the fatty acyl portion of fatty acyl CoA get into the mitochondria?
They fatty acyl group is transferred onto carnitine by carnitine acyltransferase-1
What is the sequence of events for fatty acid entry into the mitochondria?
- Fatty acyl syntehtase activates the fatty acid (outer mitochondrial membrane)
- carnitine acyltransferase-1 transfers the fatty acyl group to carnitine (outer mitochondrial membrane)
- Fatty acylcarnitine is shuttled across the inner membrane
- carnitine acyltransferase-2 transfers the fatty acyl group back to a CoA (mitochondrial matrix)
How does the liver prevent newly synthesized fatty acids from entering the mitochondria?
carnitine acyltransferase-1 is inhibited by malonyl-CoA from FA synthesis
How does insulin directly inhibit B-oxidation of fat?
by activating acetyl-CoA carboxylase (fatty acid syntheses) and increasing the malonyl-CoA concentration in the cytoplasm
What are CAT 1 and CAT 2 also known as?
CPT-1 and CPT-2
carnitine palmitoyltransferase
What does CAT 1 stand for?
carnitine acyltransferase-1
Draw a diagram on FA activation, transport, and B-oxidation.
Refer to diagram
What are symptoms of Myopathic CAT/CPT deficiency?
- muscle aches, weakness
- myoglobinuria
- provoked by prolonged exercise, especially if fasting
- biopsy: elevated muscle triglyceride
- most common form: AR, late-onset
What are some symptoms of MCAD deficiency?
- fasting hypoglycemia
- No ketone bodies (hypoketosis)
- C8-C10 acyl carnitines in blood
- vomiting
- coma, death
- AR with variable expression
- dicarboxylic aciduria
Primary treatment for MCAD deficiency?
IV glucose
What is the best prevention of symptoms for MCAD deficiency?
frequent feeding, high-carbohydrate, low fat diet
T/F. It is now believed that some cases of sudden infant death syndrome SIDS are due to MCAD deficiency?
True
What is the most common form of CAT-2/CPT-2?
myopathic form
What is the inheritance pattern of CAT-2/CPT-2 (myopathic form adolescent or adult onset)?
AR
What is the primary treatment for myopathic CAT 2/CPT 2 deficiency?
cease muscle activity and give glucose
What is another somewhat similar syndrome to CAT-2/CPT-2 deficiency?
muscle carnitine deficiency secondary to a defect in the transport system for carnitine in the muscle
Ackee, a fruit grown in Jamaica and West Africa, contains hypoglycin, which is a toxin that acts as an inhibitor of what important enzyme of metabolism?
fatty acyl-CoA dehydrogenase
Symptoms of ingestion of ackee fruit?
- Jamaican vomiting sickness and severe hypoglycemia
- sudden onset of vomiting 2-6 hours after ingesting an ackee-containing meal
- after period of prostration that may last as long as 18 hours, more vomiting may occur, followed by convulsions, coma, and even death.
What are 2 important enzymes in the propionic acid pathway?
propionyl-CoA carboxylase which requires biotin
Methylmalonyl-CoA mutase which requires vitamin B12 (cobalamin)
Why does B12 deficiency produce a peripheral neuropathy?
because of aberrant fatty acid incorpation into the myelin sheet associated with inadequate methylmalonyl-CoA mutase activity.
Excretion of methylmalonic acid indicates a differentiation between what 2 types of vitamin deficiencies?
a differentiation of B12 deficiency from folate deficiency
In the fasting state, the liver converts excess acetyl-CoA from B-oxidation of fatty acids into what ketone bodies?
acetoacetate,
3-hydroxybutyrate (β-hydroxybutyrate),
and some acetone
Cardiac and skeletal muscles and renal cortex (also the brain in prolonged fasts) metabolize acetoacetate and 3-hydroxybutyrate to which metabolic product/s?
acetyl CoA
Be able to draw a diagram for ketogenesis in the liver and ketogenolysis (extrahepatic).
Refer to diagram
Explain the mechanism by which untreated type 1 diabetes leads to ketoacidosis?
Although glucose is high, no insulin is released, HSL is active, B oxidation is not inhibited, and ketone bodies are generated
Can acetone be used as fuel in tissues?
no
Acetoacetate picked up from the blood is activated in the mitochondria by what enzyme?
succinyl-CoA acetoacetyl CoA transferase (common name thiophorase), an enzyme present only in extrahepatic tissues
Can the liver metabolize ketone bodies?
no because it doesn’t have the enzyme thiophorase
In regards to fuel for the brain, what is the time frame for when glucose goes from glucose being derived from glycogenolysis to glucose being derived from gluconeogenesis?
~12 hours
In regard to fuel for the brain, what is the time frame from when glucose is derived from gluconeogenesis to ketones derived from fatty acids?
~1 week
Why may muscle utilization of ketones be slower in chronic alcoholics?
because alcohol is converted to acetate in the liver, diffuses into the blood and oxidized by muscle as an alternative source of acetyl CoA
What are some signs and symptoms of ketoacidosis.
polyuria, dehydration, and thirst (exacerbated by hyperglycemia and osmotic diuresis)
CNS depression and coma
potential depletion of K+ (although loss may be masked by mild hyperkalemia
decreased plasma bicarbonate
breath with a sweet or fruity odor
Why may there be a potential depletion of K+ masked by a mild hyperkalemia in one with DKA?
because insulin facilitates uptake of potassium by cells, so K+ levels may be normal before DKA is treated with insulin.
Describe how the ratios shifts in a diabetic or a patient suffering alcoholic ketoacidosis, when comparing acetoacetate and B-hydroxybutyrate?
B-hydroxybutyrate predominates.
Describe how well urinary nitroprusside test detects ketoacidosis.
urinary nitroprusside test detects only acetoacetate and can dramatically underestimate the extent of ketoacidosis and its resolution during treatment
What are sphingolipids important constituents of?
cell membranes
Sphingomyelin structure.
R group is a phosphorylcholine
Cerebroside structure.
R group is a galactose or glucose
Ganglioside structure.
R group branched oligosaccharide chain terminating in the 9-carbon sugar, sialic acid (N-acetylneuraminic acid, NANA)
Be able to create a diagram on the synthesis of sphingolipids.
Refer to diagram
How are sphingolipids metabolized?
sphingolipids released when membrane is degraded are digested in endosomes after fusion with lysosomes
What is the lysosomal enzyme missing in Tay Sachs?
hexominidase A
What is the substrate that accumulates in inclusion bodies of one with Tay Sachs?
ganglioside GM2
What is the lysosomal enzyme missing in one with Gaucher disease?
glucocerebrosidase
What is the substrate that accumulates in one with Gaucher disease?
glucoserebroside
What is the lysosomal enzyme missing in one with Niemann-Pick?
sphingomyelinase
What is the substrate accumulating in one with Niemann-Pick?
sphingomyelin
Symptoms of Tay-Sachs?
- Cherry red spots in macula
- blindness
- psychomotor retardation
- death usually < 2 years of age
- exaggerated startle reflex
What are symptoms of Gaucher disease?
- Type 1 (99%): adult hepatosplenomegaly
- Erosion of bones, fractures
- Pancytopenia and thrombocytopenia
- characteristic macrophages (crumpled paper inclusions)
What are the symptoms of Niemann-Pick disease?
- May see cherry red spot in macula
- hepatosplenomegaly
- microcephaly, severe intellectual disability
- foamy macrophages with zebra bodies
- early death
Create a flow diagram on the Propionic Acid pathway.
