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Flashcards in Chapter 16 Deck (32)
1

What causes lipid mobilization?

postabsrorptive state, fatty acids used for energy

adipose tissue doesn't respond directyl to glucagon

fall in insulin activates homrone sensitive triacylglycerol lipase (HSL)--hydrolyzes triglycerides, yielding fatty acids and glycerol

epinephrine and cortisol also activate HSL

2

What happens to glycerol and fatty acids caused by lipid breakdown?

glycerol picked up by liver and converted to dihydroxyacetone phosphate (DHAP) for gluconeogenesis

fatty acids are carreid by serum albumin and distributed to tissues that can use them

3

What is niacin used for?

antihyperlipidemic drug

inhibits HSL in adipose tissue

fewer fatty acids enter the liver, VLDL isn't assembled in normal amounts

so VLDL and its product LDL are lower in serum

4

What is fatty acid oxidation?

fatty acids are oxidized in liver, muscle, adipose tissue by beta oxidation

erythrocytes (lack mitochondria) and brain (can't cross BBB) can't use fatty acids

5

How are different sized fatty acids oxidized?

short chain fatty acids (2-4 C) & medium chain fatty acids (6-12 C) diffuse freely into mitochondria to be oxidized

long chain fatty acids (14-20 C) transported into mitochondria via carnitine shuttle

very long chain fatty acids (>20 C) enter proxidsomes for oxidation

6

How are long chain fatty acids processed in the mitochondria?

long chain fatty acids actiated by fatty acyl CoA synthase on outer mitochondrial membrane by attaching CoA

fatty acyl portion transferred onto carnitine by carnitine acyltransferase-1 (inhibited by malonyl CoA)

--insulin indirectly inhibits beta oxidation by activaing acetyl CoA carboxylase (FA synthesis) and increasing malonyl CoA; glucagon reverses this process)

carnitine acyltransferase 2 transfers fatty acyl group back to CoA (mitochondrial matrix)

 

7

What is beta oxidation in the mitochondria?

beta oxidation reverses the process of fatty acid synthesis by oxidizing and releasing unites of acetyl CoA

--each cycle releases one acetyl CoA and reduces NAD and FAD

FADH2 and NADH are oxidized in the ETC providing ATP

muscle, adipose tissue: acetyl CoA enters TCA 

liver: ATP used for gluconeogenesis; acetyl CoA stimulates gluconeogenesis by actiating pyruvate carboxylase

8

What is the product of beta oxidation of palmitate?

8 acetyl CoA

9

What occurs in liver beta oxidation during fasting state?

.iver roduces more acetyl CoA from beta oxidation than is used in TCA

much of acetyl CoA is used to syntehsze ketone bodies (two acetyl CoA linked together) that is released into blood for other tissues 

10

What are the two common genetic deficiencies of fatty acid oxidation?

medium chain acyl CoA dehdyrogenase (MCAD) deficiency: primary etiology hepatic

myopathic carnitine acyltransferase (CAT/CPT) deficiency: primary etiology myopathic

11

What is MCAD deficiency?

non ketotic hypoglycemia associated with block in hepatic beta oxidation

during fasting: hypoglycemia profound due to lack of ATP to support gluconeogenesis

decreased acetyl CoA lowers pyruvate carboxylase activity and limits ketogenesis

symptoms: profound fasting hypoglycermia, low to bsent ketons, lethargy, coma, death if untreated, C8-C10 acyl carnitines in blood, episode may be provoked by overnight fast in infant, older child, often provoked by illness (flu) that cuases loss of appetite and vomiting

treatment: IV glucose

prevention: frequent feeding, high carbohydrate low fat diet

--occurs during metabolic stress by severe fasting, exercise or infeciton (conditions iwth high demands on fatty acid oxidation)

12

What is ackee?

hypoglycin

toxin that acts as inhibitor of fatty acyl CoA dehydrogenase

Jamaican vomiting sickness and severe hypoglycemia

convulsions, coma and death

13

What symptoms are suggestive of block in beta oxidation?

severe hypoglycemia and absense of ketosis (hypoketosis)

14

What is CAT/CPT deficiency?

defect in muscle specific CAT/CPT gene

autosomal recessive condition with late onset

symptoms: muscle aches, mild to severe weakness, rhabdomyolysis, myoglobinuria, red urine, episode provoked by prolonged exercise especially after fasting, cold or assocaited stress, symptoms exacerbated by high fat low carbohydrate diet

--muscle biopsy shows elevated muscle TGL detected as lipid droplets in the cytoplasm

treatment: cease muscle activity and give glucose

15

What is the propionic acid pathway?

even carbon FA yield two acetyl CoA

odd carbon FA yield one acetyl CoA and one propionyl CoA

--converted to succinyl CoA (TCA intermediate) then malate to enter cytoplasm and gluconeogenesis

exception to rule that FA can't be converted to glucose

16

What does propionyl CoA carboxylase require?

biotin

17

What does methylmalonyl CoA mutase require?

vitamin B12 cobalamin

 vitamin B12 deficiency: megaloblastic anemia (same type seen in folate deficiency)

--produces peripherla neuropathy becuase of aberrant FA incorporation into myelin sheets assocaited with inadequate methylmalonyl CoA mutase activitiy

excretion of methylmalonic acids indicates a vitamin B12 deficiency rather than folate

18

What is ketone body metabolism?

fasting state, liver converts excess acetyl CoA from beta oxidation of fatty acids into ketone bodies, acetoacetate, and 3 hydroxybutyrate (beta hydroxybutyrate)--used by extrahepatic tissues

cardiac, skeletal muscle, renal cortex: metabolize acetoacetate and 3 hydroxybutyrate to acetyl CoA

during fast, muscle metabolizes ketones as rapidly as liver releases them so don't accumulate in blood

after week fo fasting, ketones reach concnetration in blood high enough for brain to begin metabolizing them

--if ketones increased too much in blood-->ketoacidosis

19

What is ketogenesis?

occurs in mitochodnria 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 is then reduced to 3 hydroxybutyrate

acetone=minor side product; strong odor (sweet, fruity) to breath--diagnostic for ketoacidosis

20

What is ketogenolysis?

acetoacetate is picked up from blood and activated in mitochondria by succinyl CoA acetoacetyl CoA transferase (enzyme is only in extrahepatic tissues)

3-hydroxybutyrate is first oxidized to acetoacetate

liver lacks enzyme so can't metabolize ketone bodies

21

What is ketogenolysis in the brain?

12 hours: glucose derived from liver glycogenolysis to glucose derived from gluconeogenesis

1 week: glucose derived from gluconeogensis to ketones derived from fatty acids

in the brain: ketones are metabolized to acetyl CoA and pyruvate dehydrogenase is inhibited

glycolysis and glucose uptake in brain decreased

switch spares body protein by allowing the brain to indirectly metabolize fatty aicds as ketone bodies

22

What is ketoacidosis?

type 1 insulin dependent diabetes mellitus not adequately treated with inuslin: fatty acid release from adipose tissue and ketone sytnehsis in liver exceed the ability of other tissues to metabolize them

ketoacidosis may occur

infection or trauma (causing an increase in coritosl and epinephrine) may precipitate an episode of ketoacidosis

NIDDM: less likely to have ketoacidosis; can occur after infection or trauma

23

What is ketoacidosis in alcoholics?

chronic hypoglycemia, often prevent in chronic alocholism favors fat release from adipose

ketone production increases in the liver, but utilization in muscle may be slower than normal because alcohol is converted to acetate in the liver, diffuses into the blood and oxidized by muscle as an alternative source of acetyl CoA

24

What is associated ketoacidosis?

polyuria, dehydration, and thrist (exacerbated by hyperglycemia and osmotic diuresis)

CNS depression and coma

potential depletion of K+ (although loss may be masked by a mild hyperkalemia)

decreased plasma bicarbonate

breath with a sweet or fruity odor, acetone

25

What occurs with normal and pathologic ketosis?

normal ketosis: acetoacetate and beta hydroxybutyrate are formed in approximately equal quantities 

pathologic conditions (diabetes and alcoholism) ketoacidsosis --> beta hydroxybutyrate is higher than acetoacetate

26

What are spingolipids?

important constituents of cell membranes 

contain no glycerol

hydrophilic region and two fatty acid derived hydrophobic tails

27

What are the classes of sphingolipids?

sphingomyelin: phosphorylcholine

cerebrosides: galactose or glucose

gangliosides: branched oligosaccharide chains terminating in the 9-carbon sugar, sialic acid (N-acetylneuraminic acid, NANA)

28

What is Tay-Sachs?

29

What is Niemann-Pick?

30

What is Gaucher?

Ashkenazic Jew, lethargic (anemia), bruise easily (low platelet count), massive hepatomegaly, splenomegaly, pallow, hematologic complications

cytoplasm: PAS stain positive

glucocerebrosisidases: low

wrinkled paper cytoplasm

in brain: glucocerebroside arises from breakdown of old red and white cells 

in brain: glucocerebroside arises from turnover of ganglioside during brain development and formation of the myelin sheath

31

What is Fabry disease?

spingolipidoses (usually autosomal recessive) but this is X-linked recessive

mutation inthe gene encoding the lysosomal enzyme a-galactosidase

ceramide trihexoside accumulates inthe lysosome

symptoms: burning sensations in the hands which gets worse with exercise and hot weather; small, raised reddish purple blemishes on skin (angiokeratomas); eye manifestations, especially cloudiness of the cornea; impaired arterial circulation and increased risk of heart attack or stroke; enlargement of heart and kidneys

usually survival into adulthood but with increased risk of CVD, stroke

renal failure is often cause of death

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