Lipid Mobilization and Catabolism Flashcards
1
Q
human adipose tissue doesn’t respond directly to glucagon. Instead, the fall in insulin:
A
- activates a hormone-sensitive TG lipase (HSL)
- HSL is active when phosphorylated
- HSL is induced by cortisol
- activated by decreased insulin, increased epinephrine
- the HSL hydrolyzes TG, yielding FA and glycerol
- epinephrine and cortisol also activate HSL
2
Q
How does the Atkins diet work?
A
- high fat, high protein, NO carbs
- this means there’s low insulin, so HSL (in adipose tissue) is not deactivated
- HSL is active when phosphorylated, when insulin levels fall, HSL is phosphorylated
- HSL is induced by cortisol
- HSL hydrolyzes TG, yielding FA and glycerol
- 2 problems w Atkins:
1. excessive N
2. high ketone bodies (if diet is prolonged) - you must drink a lot of water of you’ll develop ketonuria
3
Q
What are the 3 sources the liver can use for gluconeogenesis during fasting
A
- Glycerol from Adipose tissue
- alanine form muscle
- lactate from RBC
4
Q
- Niacin is a commonly used antihyperlipidemic drug
- in large doses, it works by
A
inhibiting HSL in adipose tissue
- with fewer FA entering the liver, VLDL will not be assembled in normal amounts
- so both VLDL (carrying TG and cholesterol) and its product, LDL will be lower in serum
5
Q
Tay- Sachs
- lysosomal enzyme missing:
- substrate accumulating in inculsion body:
- symptoms
A
- genetic deficiency in sphingolipid catabolism
- Hexosaminidase A deficiency
- 4 nucleotide insertion splicing defect
- Ganglioside GM2 (galactosamine) accumulates in inclusion bodies
- cherry red spots in macula
- blindness
- psychomotor retardation
- death usually before 2yo (before hepatosplenomegaly can develop)
- startle reflex more pronounced than normal baby
6
Q
Gaucher’s Diasease
- lysosomal enzyme missing:
- substrate accumulating in inculsion body:
- symptoms
A
- genetic deficiency in sphingolipid catabolism
- glucocerebrosidase deficiency
- gene has been cloned and can be given via IV, but $$$
- glucocerebroside accumulates in lysosomes
- except for the brain, glucocerebroside arises mainly fro the breakdown of old RBC and WBC.
- in the brain, glucocerebroside arises from the turnover of gangliosides during brain development and formation of the myelin sheath
- Type I: ADULT hepatosplenomegaly
- hepatosplenomegaly
- pallor
- erosion of bones, fractures
- pancytopenia or thrombocytopenia
- (easy bruising due to low platelet count)
- lethargy (due to anemia)
- crumpled paper inclusions (characteristic macrophages)
- carbohydrate positive staining
7
Q
Niemann-Pick Disease
- lysosomal enzyme missing:
- substrate accumulating in inculsion body:
- symptoms
A
- genetic deficiency in sphingolipid catabolism
- sphingomyelinase deficiency
- sphingomyelin accumulates in inclusion bodies
- may (or may not) see cherry red spot in macula
- hepatosplenomegaly
- microcephaly, severe mental retardation
- zebra bodies in inclusions
- foamy macrophages
- early death
8
Q
beta oxidation
A
- fat release from adipose
- occurs in liver, muscle and adipose
- Short chain FA (2-4C) and Medium chain FA (6-12C) diffuse freely into mitochondria to be oxidized
- LCFA (14-20C) are transported into mito by carnitine shuttle
- VLCFA (more than 20C) enter peroxisomes for oxidation
- HSL: hydrolyzes TG, yielding FA and glycerol
- induced by cortisol
- activated by decreased insulin, increased epinephrine
- neither brain nor RBC can use FA (bc RBC don’t have mitochondria, and FA can’t cross BBB)
9
Q
Transport of FA into mitochondria of target tissues
A
- carnitine shuttle
- Short chain FA (2-4C) and Medium chain FA (6-12C) diffuse freely into mitochondria to be oxidized
- LCFA (14-20C) are transported into mito by carnitine shuttle
- VLCFA (more than 20C) enter peroxisomes for oxidation
- rate-limiting enzyme: carnitine acyltransferase-1 (CAT-1, CPT-1)
- inhibited by malonyl CoA (increases during FA synthesis
10
Q
Medium-Chain acyl CoA dehydrogenase (MCAD) Deficiency
A
- non-ketotic hypoglycemia should be strongly assoc with a block in hepatic beta-oxidation
- primary etiology hepatic
- profound fasting hypoglycemia
- hypoketosis (no ketone bodies)
- C8-10 Acylcarnitines in blood (hyperchylomicronemia)
- vomiting
- lethargy, coma, death
- AR with variable expression
- associated with SIDS (may be provoked by overnight fast in infant)
- dicarboxylic aciduria
- Primary Tx: IV glucose
- prevention: frequent feeding, high carb, low fat diet
- will act up in times of stress (i.e. fasting, exercise, infection)
- ex) older kid whose symptoms started following illness that causes loss of appetite and vomiting
11
Q
Myopathic CAT-2 (CPT-2) Deficiency
- carnitine acyltransferase-2 (CAT-2) aka carnitine palmitoyl transferase-2 (CPT-2)
A
- defect in carnitine transport
- primary etiology myopathic (although all tissues with mito have carnation acyltransferase, the MC form of this genetic deficiency is myopathic, due to a defect in the muscle-specific CAT/CPT gene)
- extreme muscle weakness assoc w endurance exercise and/or exercise after prolonged fasting*
- rhabdomyolysis and myoglobinuria (coca-cola urine)
- sx may be exacerbated by high-fat, low carb diet
- MC form: AR, late onset
- Biopsy: elevated muscle TG detected as lipid droplets in cytoplasm
- Tx: stop activity and give glucose
1. Epinephrine is secreted during exercise and it activates HSL
2. FA from blood taken up by m cells, but carnation shuttle inefficient, so they’re not getting into mito
3. so not enough ATP causes muscle weakness and pain - similar to McArdle’s, need m. biopsy to distinguish
12
Q
myopathic carnitine deficiency
A
- similar to CAT-1 deficiency, but less severe
13
Q
Ketone Bodies
A
- formed from excess hepatic acetyl CoA during fasting: acetoacetate, 3-hydroxybutyrate, acetone (not metabolized further
- oxidized in cardiac skeletal muscle, renal cortex and brain (prolonged fast)
14
Q
Sphingolipids
A
- constituents of lipid bilayer membranes:
1. sphingomyelin: ceramide + P and choline
2. Cerebroside: ceramide + glc or gal
3. gangliosides/glycolipids: ceramide + oligosaccharides + sialic acid
15
Q
Fatty acyl synthetase
A
- LCFA (14-20C) must be activated and transported into mito by a carnitine shuttle
- Fatty acyl synthetase is located on the outer mito membrane
- it activates LCFA by attaching CoA
- the fatty acyl portion is then transferred onto carnation by carnation acyltransferase-1 for transport into the mito
16
Q
Steps involved in FA entry into mitochondria
A
- LCFA (14-20C) must be activated and transported into mito by a carnitine shuttle
1. FASynthetase (outer mito membrane) activates the FA
2. Carnitine Acyltransferase-1 (outer mito membrane) transfers the fatty acyl group to carnitine
3. Fatty acylcarnitine is shuttled across the inner membrane
4. carnitine acyltransferase-2 (mito matrix) transfers the fatty acyl group back to a CoA
17
Q
Carnitine Acyltransferase-1
- carnitine acyltransferase-1 (CAT-1) aka carnitine palmitoyl transferase-1 (CPT-1)
A
- involved in FA entry into mitochondria
- located on the outer mito membrane
- transfers the fatty acyl group to carnitine
- inhibited by malonyl CoA from FA synthesis and thereby prevents newly synthesized FA from entering the mito
- Insulin directly inhibits beta oxidation by activating acetyl-CoA carboxylase (FA synthesis) and increasing the malonyl-CoA concentration in the cytoplasm
- glucagon reverses this process
18
Q
Carnitine Acyltransferase-2
- carnitine acyltransferase-2 (CAT-2) aka carnitine palmitoyl transferase-2 (CPT-2)
A
- involved in FA entry into mitochondria
- located in the mitochondrial matrix
- transfers the fatty acyl group back to a CoA
19
Q
How do Insulin and Glucagon regulate beta oxidation?
A
- Insulin directly inhibits beta oxidation by:
- activating acetyl-CoA carboxylase (FA synthesis) and increasing the malonyl-CoA concentration in the cytoplasm
- malonyl CoA from FA synthesis inhibits carnitine acyltransferase-1 (thus prevents the transfer of fatty acyl group back to carnitine) and
- thereby prevents newly synthesized FA from entering the mito - glucagon reverses this process
20
Q
Each 4-step cycle of beta oxidation releases
A
- 1 acetyl CoA
- and reduces NAD and FAD (producing NADH and FADH2)
- the NADH and FADH2 are oxidized in the ETC to make ATP
21
Q
In the liver, Acetyl CoA stimulates
A
- gluconeogenesis by activating pyruvate carboxylase
- remember, acetyl CoA can’t be converted back to glucose
22
Q
Jamaican vomiting sickness
A
- caused by ackee, a fruit that grows in jamaica and W africa
- contains hypoglycin, a toxin that acts as an inhibitor of fatty acyl cos dehydrogenase
- causes sudden onset vomiting 2-6h after ingesting
- after 18h more vomiting may occur followed by convulsions, coma and death
23
Q
What is a short chain FA?
A
2-4C
24
Q
Classes of sphingolipids and their hydroPHILIC groups
A
- sphingomyelin: phosphorylcholine
- cerebrosides: gaalctose or glucose
- gangliosides: branched oligosaccharide chains terminating in the 9C sugar, silica acid (N-acetylnuraminic acid, NANA)
25
Q
Methylmalonyl CoA Mutase
A
- involved in the propionic acid pathway
- found in mitochondria
- converts methylmalonyl CoA to succinyl CoA
- requires Vitamin B12
- if deficient, results in peripheral neuropathy
- bc abberent FA are incorporated into myelin sheets
- this is seen in Vitamin B12 deficiency
26
Q
What is a Very long chain FA?
A
- more than 20 C
- these enter peroxisomes for oxidation
27
Q
Propionyl CoA Carboxylase
A
- involved in the propionic acid pathway
- found in mitochondria
- converts propionyl CoA to methylmalonyl CoA (what accumulates in VB12 deficiency or if there is a mutation in methylmalonyl CoA mutase)
- an ABC enzyme. Requires:
A: ATP
B: Biotin
C: CO2
28
Q
Fabry Disease
A
- the only x-linked recessive deficiency in sphingolipid catabolism
- mutation lysosomal enzyme alpha-galactosidase
- ceramide trihexoside accumulates in the lysosomes
- presents during childhood/adolescence
- burning sensations in hands that get worse w exercise/hot weather
- small, raised reddish-purple blemishes on skin (angiokeratomas)
- eye manifestations: esp cloudiness of cornea
- impaired arterial circulation and increased risk of MI/Stroke
- enlargement of heart and kidneys
- often survive into adulthood, but with increased risk of cardiovascular disease/stroke
- renal failure is often COD
29
Q
What is a medium chain FA?
A
6-12C
30
Q
Hemophilia:
- lab symptoms
A
- excessive bleeding
- increased PTT
- correction of the PTT with addition of normal serum
- MC types of hemophilia:
1. Hemophilia A: def in clotting factor VIII
2. Hemophilia B (Christmas Disease): def in clotting factor IX - both are x-linked recessive diseases
31
Q
What is a long chain FA?
A
14-20C
32
Q
how do you differentiate between folate and vitamin B12 deficiency?
A
- both cause megaloblastic anemia
- Methylmalonyl CoA mutase converts methylmalonyl CoA to succinyl CoA
- requires Vitamin B12
- in Vitamin B12 deficiency, methylmalonyl CoA accumulates and is found in the urine: methylmalonic aciduria
- results in peripheral neuropathy
- bc abberent FA are incorporated into myelin sheets
33
Q
Propionic Acid Pathway
A
- in the last cycle of beta-oxidation:
- FA with an even # of C yield 3 acetyl-CoA (from the 4C fragment remaining)
- FA with an odd # of C yield one acetyl-CoA and one propionyl CoA (from the 5C fragment remaining)
- propionyl CoA is converted to succinyl CoA (a CAC intermediate)
- succinyl CoA can form malate and enter the cytoplasm and gluconeogenesis
34
Q
When does ketogenesis occur
A
- in the mitochondria of hepatocytes when excess acetyl-CoA accumulates in the fasting state
- HMG-CoA synthase forms HMG-CoA and
- HMG-CoA lyase breaks HMG-CoA into acetoacetate
- which can be reduced to 3- hydroxybutyrate
35
Q
Where does the characteristic fruity odor associated with ketoacidosis come from?
A
- acetone is minor side product formed nonenzymatically during ketogenesis
- but it is not used as a fuel in tissues
- ketosis = ketone bodies in blood (leads to acidosis)
- ketone bodies in urine = ketonuria
- remember: liver can’t metabolize ketone bodies
36
Q
Fuel for the Brain
A
- Glucose derived from liver glycogenolysis to glucose derived from gluconeogenesis (approx 12 hrs)
- Glucose derived from gluconeogenesis to ketones derived from FA (approx 1 week)
- in the brain, when ketones are metabolized to acetyl-CoA, PDH is inhibited
- this decreases glycolysis and glucose uptake in the brain
- this spares body protein (which would otherwise be broken down to form glucose by gluconeogenesis in the liver) by allowing the brain to indirectly metabolize FA as KB
37
Q
ketoacidosis
A
- in T1 Diabetics not adequately treated with insulin:
- FA release from adipose and KB synthesis in the liver exceed the ability of other tissues to metabolize them, causing severe ketoacidosis
- infection/trauma (causing an increase in cortisol and epinephrine) may cause
- T2 Diabetics are less likely to show ketoacidosis, but may after infection/trauma
- Alcoholics can also develop ketoacidosis
38
Q
Ketoacidosis in alcoholics
A
- Chronic HYPOglycemia (common in chronic alcoholism) favors fat release from adipose
- KB production increase in the liver,
- but utilization in muscle may be slower than normal bc alcohol is converted to acetate in the liver,
- diffuses into the blood, and is oxidized by muscle as an alternative source of Acetyl CoA
39
Q
Sx of ketoacidosis
A
- polyuria, dehydration and thirst (exacerbated by HYPERglycemia and osmotic diuresis)
- CNS depression and coma
- potential depletion of K+ (although loss may be masked by a milk HYPERkalemia)
- decreased plasma bicarb
- breath with a sweet or fruity odor, acetone
- remember, in DKA you’ll give insulin, and insulin causes K+ to be absorbed by cells
40
Q
Relationship btw K+ and Insulin
A
- Insulin causes Potassium to shift into the cells thereby decreasing the extracellular K level.
- That’s why insulin is used in the treatment of hyperkalemia.
- Level of Potassium in the serum also affects insulin secretion from the pancreas.
- Because the beta cells have an ATP dependent K channel
- which, when closed, leads to retained K inside the beta cell
- which favors depolarization
- thereby enhancing Calcium mediated release of secretory granules.
- Therefore, in hyperkalemia more K will enter the beta cell and insulin secretion will increase and
- conversely in hypokalemia the K ions are more likely to leave the beta cell and so insulin secretion will decrease.
41
Q
Cortisol stimulates transcription of the PEP Carboxykinase gene in the liver but NOT
A
Cortisol stimulates transcription of the PEP Carboxykinase gene in the liver but NOT in adipose tissue
42
Q
Retinal pallor sparing the macula
A
- Cherry red spot
- seen in Lysosomal Storage Diseases Tay-Sachs and Niemann Pick
- NP also has hepatosplenomegaly
- TS: missing hexosaminidase A –> accumulate Ganglioside GM2 (also have blindness, psychomotor retardation, startle reflex and death by 2y)
- NP: missing sphingomyelinase accumulate sphingomyelin–> zebra body inclusions (lamellar lipid deposits in lipid-laden cells) and foamy macrophages aka sea blue histiocytes (sphingomyelin accumulation in macrophages) and microcephalic, mental retardation, and death by 3
43
Q
In fasting state, liver coverts
A
- In fasting state, liver coverts excess acetyl coA (from beta-oxidation of FA) into ketone bodies
- Ketone Bodies: acetoacetate and 3-hydroxybutyrate (beta-hydroxybutyrate)
- cardiac, skeletal m, and renal cortex metabolize these into acetyl-CoA
- normally, during fasting muscle metabolizes KB as fast as liver produces them (prevents accumulate in blood)
- but after 1 week fasting: accumulate in blood enough for brain to begin using them
- if accumulate too much –> keto acidosis
44
Q
Symptoms of ketoacidosis
A
- pollution, dehydration, thirst (exacerbated by hypoglycemia and osmotic dieresis)
- CNS depression and coma
- potential depletion of K+ (although loss may be masked by mild hyperK
- decreased plasma bicarbonate
- fruity breath odor (acetone)
