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tsomkapQ > Lipid Mobilization and Catabolism > Flashcards

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
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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
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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
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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
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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
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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
    1. 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
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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
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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)
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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
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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
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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
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12
Q

myopathic carnitine deficiency

A
  • similar to CAT-1 deficiency, but less severe
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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)
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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
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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
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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
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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
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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
  1. 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
  2. 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)

tsomkapQ (117 decks)

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