Lipid Mobilization and Catabolism Flashcards Preview

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Flashcards in Lipid Mobilization and Catabolism Deck (44)
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1

human adipose tissue doesn't respond directly to glucagon. Instead, the fall in insulin:

- 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

How does the Atkins diet work?

- 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

What are the 3 sources the liver can use for gluconeogenesis during fasting

- Glycerol from Adipose tissue
- alanine form muscle
- lactate from RBC

4

- Niacin is a commonly used antihyperlipidemic drug
- in large doses, it works by

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

Tay- Sachs
- lysosomal enzyme missing:
- substrate accumulating in inculsion body:
- symptoms

- 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

Gaucher's Diasease
- lysosomal enzyme missing:
- substrate accumulating in inculsion body:
- symptoms

- 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

7

Niemann-Pick Disease
- lysosomal enzyme missing:
- substrate accumulating in inculsion body:
- symptoms

- 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

beta oxidation

- 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

Transport of FA into mitochondria of target tissues

- 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

Medium-Chain acyl CoA dehydrogenase (MCAD) Deficiency

- 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

Myopathic CAT-2 (CPT-2) Deficiency

- carnitine acyltransferase-2 (CAT-2) aka carnitine palmitoyl transferase-2 (CPT-2)

- 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

myopathic carnitine deficiency

- similar to CAT-1 deficiency, but less severe

13

Ketone Bodies

- 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

Sphingolipids

- 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

Fatty acyl synthetase

- 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

Steps involved in FA entry into mitochondria

- 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

Carnitine Acyltransferase-1

- carnitine acyltransferase-1 (CAT-1) aka carnitine palmitoyl transferase-1 (CPT-1)

- 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

Carnitine Acyltransferase-2

- carnitine acyltransferase-2 (CAT-2) aka carnitine palmitoyl transferase-2 (CPT-2)

- involved in FA entry into mitochondria
- located in the mitochondrial matrix
- transfers the fatty acyl group back to a CoA

19

How do Insulin and Glucagon regulate beta oxidation?

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

Each 4-step cycle of beta oxidation releases

- 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

In the liver, Acetyl CoA stimulates

- gluconeogenesis by activating pyruvate carboxylase
- remember, acetyl CoA can't be converted back to glucose

22

Jamaican vomiting sickness

- 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

What is a short chain FA?

2-4C

24

Classes of sphingolipids and their hydroPHILIC groups

- 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