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
Methylmalonyl CoA Mutase
- 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
What is a Very long chain FA?
- more than 20 C
| - these enter peroxisomes for oxidation
27
Propionyl CoA Carboxylase
- 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
Fabry Disease
- 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
What is a medium chain FA?
6-12C
30
Hemophilia:
| - lab symptoms
- 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
What is a long chain FA?
14-20C
32
how do you differentiate between folate and vitamin B12 deficiency?
- 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
Propionic Acid Pathway
- 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
When does ketogenesis occur
- 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
Where does the characteristic fruity odor associated with ketoacidosis come from?
- 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
Fuel for the Brain
- 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
ketoacidosis
- 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
Ketoacidosis in alcoholics
- 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
Sx 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 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
Relationship btw K+ and Insulin
- 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
Cortisol stimulates transcription of the PEP Carboxykinase gene in the liver but NOT
Cortisol stimulates transcription of the PEP Carboxykinase gene in the liver but NOT in adipose tissue
42
Retinal pallor sparing the macula
- 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
In fasting state, liver coverts
- 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
Symptoms of ketoacidosis
- 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)
