Biochem

Question 1

What is the major fuel source for the fetal heart?

Answer 1

glucose

The fetal heart depends upon anaerobic glycolysis and oxidation of pyruvate or lactate to CO2 for energy production. Fatty acids are not used to the same extent in fetal heart as in adult.
The fetal heart has much larger storage of glycogen than adult heart.

Question 2

How does decreased pH affect PFK in the adult heart?

Answer 2

Acidosis inhibits PFK. During O2 deprivation, as in ischemia, higher levels of AMP activate PFK to generate ATP by anaerobic glycolysis. BUT lactic acid production from anaerobic glycolysis further decreases pH, and therefore PFK is inhibited to protect the heart from acidity.

Question 3

What is the rate limiting enzyme for fatty acid oxidation?

Answer 3

carnitine palmitoyl transferase 1
It is inhibited by malonyl-CoA, which is regulated by ACC (acetyl-CoA carboxylase) and malonyl-CoA decarboxylase (MCD)
High levels of acetyl-CoA inhibit ACC and prevent fatty acid oxidation.
Acetyl-CoA enters the TCA to produce NADH2, FADH2 and CO2. These provide reducing equivalents for ETC (proton gradient across IMM drives ATP production)

Question 4

What is myocardial stunning?

Answer 4

Temporary contractile dysfunction as a result of ischemia or hypoxemia. Can be reversed with adrenergic stimulation

Question 5

What is myocardial hibernation?

Answer 5

chronic downregulation of contractile activity from chronic exposure to low flow myocardial perfusion

Question 6

What is the rate-limiting step in cholesterol synthesis?

Answer 6

reduction of HMG-CoA to mevalonate by HMG-CoA reductase

Question 7

VLDL shuttles cholesterol to other tissues to be used for?

Answer 7

• synthesis of membranes
• synthesis of hormones
• biosynthesis of Vitamin D

Question 8

How do statins decrease cholesterol?

Answer 8

statins inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. When cholesterol levels fall, scap:SREBP moves to the Golgi for activation, and transcription of the LDL receptor is stimulated. Increased LDL receptors on the hepatocyte membrane increase removal of LDL from the bloodstream, ultimately preventing saturation of receptors leading to availability of LDL for oxidation by endothelial macrophages.

Question 9

What is CEPT?

Answer 9

cholesteryl ester transfer protein: exchanges one molecule of cholesteryl ester in HDL for one triglyceride of VLDL. HDL clearance is enriched when it is triglyceride rich, by action of lipase.

Question 10

concentration of substrate required to reach 1/2 Vmax

Answer 10

Km

Question 11

What regulates the uptake of fatty acids into mitochondria?

Answer 11

level of malonyl-CoA

when malonyl-CoA is low, FA oxidation is stimulated

Question 12

two main hormones that influence energy metabolism

Answer 12

1. catecholamines

2. insulin

Question 13

During ischemia, ATP generated is used primarily for what?

Answer 13

maintain gradients of ion channels
*this depletes ATP needed for muscle contraction and irreversible damage happens within 40-60 min of ischemia, starting from ENDOcardium to EPIcardium

Question 14

rate limiting enzyme for glucose oxidation

Answer 14

pyruvate dehydrogenase

it is phosphorylated by pyruvate dehydrogenase kinase (PDK4 is cardiac isozyme -> pharm target)

Question 15

markers of MI

Answer 15

1. myoglobin in sera is nonspecific but from muscle damage or potential renal failure; elevates within 2 hours of symptom onset; negative predictor; elevated for half a day to 1 day
2. Troponin T/I is a late marker for myocardial injury; elevates within 3-5 hours of injury; stays elevated up to 2 weeks (TnT)
3. CK > 5% elevated within 3-4 hours and stays elevated 2-4 days

Question 16

binds to actin, influencing its conformation and preventing actin-myosin interaction necessary for contraction

Answer 16

troponin-I

Question 17

causes cardiomyopathy that develops in teen years

Answer 17

mutation of phospholamban

phospholamban is phosphorylated by protein kinase A which inhibits its activity. Inhibition increases HR. When it is not inhibited, its association with SERCA2a (mediates calcium sequestration) is increased which decreases calcium pumping ability and increases relaxation time -> decreased rate of contraction-> heart failure

Question 18

source of carbons of cholesterol

Answer 18

acetyl-CoA

Question 19

sources of acetyl-CoA

Answer 19

beta oxidation of FA
oxidation of ketogenic amino acids
pyruvate dehydrogenase reaction

Question 20

Where is cholesterol synthesized?

Answer 20

cytosol

Question 21

How many NADPH are needed for the reduction of HMG-CoA?

Answer 21

2

Question 22

How many ATP are required to transfer phosphate groups to mevalonate in isoprene formation?

Answer 22

3

Question 23

In formation of the squalene epoxide, what other reactants are required?

Answer 23

O2 -> formation of the epoxide

NADPH x 2-> forms water with remaining O atom

Question 24

What is the product of cyclization of squalene?

Answer 24

lanosterol

Question 25

Cholesterol is excreted from the hepatocyte in 3 forms:

Answer 25

1. cholesterol esters 2. bile salts 3. bile acids

Question 26

Cholesterol is packaged into what in the intestine?

Answer 26

chylomicrons

Question 27

Cholesterol is packaged into what in the liver?

Answer 27

VLDL note: VLDL is metabolized to IDL and then to LDL

Question 28

major function of HDL. Why is this important?

Answer 28

transport of cholesterol back to the liver -> reverse cholesterol transport -reduces the availability of LDL for macrophages to scavenge

Question 29

hormones synthesized from cholesterol

Answer 29

aldosterone cortisol sex hormones

Question 30

importance of ApoCII

Answer 30

HDL transfers ApoE and ApoCII to chylomicrons and VLDL. ApoCII activates lipolipase in cardiac muscle. Lipolipase releases FA from chylomicron triacylglycerides for use by myocytes for energy production. Note: chylomicron remnants still have ApoE which binds to hepatocyte receptors for endocytosis

Question 31

HDL is produced by

Answer 31

1. liver with several apoproteins 2. budding of apoproteins from chylomicrons and VLDL as lipolipase digests them 3. free ApoI which acquires cholesterol and phospholipids from other lipoproteins and cell membranes

Question 32

proteins the LDL receptor recognizes

Answer 32

1. ApoB100 2. ApoE allows it to bind VLDL, IDL, chylomicron remnants and LDL

Question 33

What causes formation of homocysteine?

Answer 33

mutated cystathionine beta-synthase deficiency in vitamin B6 Elevated homocysteine in the blood (homocystinemia) promotes thrombosis

Question 34

phagocytosis of LDL is accelerated by

Answer 34

oxidative modification of ApoB

Question 35

what protein is in VLDL, LDL and IDL?

Answer 35

apoB100

Question 36

What protein is associated with HDL?

Answer 36

apoA

Question 37

What is the primary goal in management of patients with metabolic syndrome?

Answer 37

reduction of risk of clinical atherosclerosis

Question 38

3 major risk factors of metabolic syndrome

Answer 38

1. elevated LDL 2. HTN 3. elevated fasting glucose

Question 39

How does a statin decrease LDL?

Answer 39

limits cholesterol production by targeting HMG-CoA reductase and inhibiting it. Decreased intracellular cholesterol production results in increased expression of LDL receptors on the hepatocyte membrane, removing LDL from circulation

Question 40

How does fibric acid derivative improve lipid profiles?

Answer 40

it binds to a nuclear transcription regulator (peroxisome proliferator-activated receptor-alpha-> PPAR-alpha) and activates it. This is expressed in liver and skeletal muscle. Results in increased lipolipase activity in muscle and hepatocytes, increasing clearance of VLDL. Increases ApoA expression and therefore increases HDL. Get large reduction in triglycerides, medium increase in HDL and small reduction in cholesterol and LDL.

Question 41

How do cholestyramine, colestipol and colesevelam decrease LDL?

Answer 41

inhibition of reabsorption of bile acids in the jejunum and ileum. More cholesterol is converted to bile acids leading to lower intracellular cholesterol and upregulation of LDL receptors and increasing clearance from bloodstream. Little effect on HDL

Question 42

How does ezetimibe improve cholesterol?

Answer 42

inhibits cholesterol absorption from the jejunum | usually used in conjunction with a statin

Question 43

How does niacin improve cholesterol?

Answer 43

- Activates lipolipase (increases VLDL clearance) - reduces hepatic production of VLDL by inhibiting lipase in adipose tissue and decreasing the free fatty acids available to the liver - reduces catabolism of HDL (decreases apoA clearance)