Biochem Flashcards
What is the major fuel source for the fetal heart?
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.
How does decreased pH affect PFK in the adult heart?
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.
What is the rate limiting enzyme for fatty acid oxidation?
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)
What is myocardial stunning?
Temporary contractile dysfunction as a result of ischemia or hypoxemia. Can be reversed with adrenergic stimulation
What is myocardial hibernation?
chronic downregulation of contractile activity from chronic exposure to low flow myocardial perfusion
What is the rate-limiting step in cholesterol synthesis?
reduction of HMG-CoA to mevalonate by HMG-CoA reductase
VLDL shuttles cholesterol to other tissues to be used for?
- synthesis of membranes
- synthesis of hormones
- biosynthesis of Vitamin D
How do statins decrease cholesterol?
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.
What is CEPT?
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.
concentration of substrate required to reach 1/2 Vmax
Km
What regulates the uptake of fatty acids into mitochondria?
level of malonyl-CoA
when malonyl-CoA is low, FA oxidation is stimulated
two main hormones that influence energy metabolism
- catecholamines
2. insulin
During ischemia, ATP generated is used primarily for what?
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
rate limiting enzyme for glucose oxidation
pyruvate dehydrogenase
it is phosphorylated by pyruvate dehydrogenase kinase (PDK4 is cardiac isozyme -> pharm target)
markers of MI
- 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
- Troponin T/I is a late marker for myocardial injury; elevates within 3-5 hours of injury; stays elevated up to 2 weeks (TnT)
- CK > 5% elevated within 3-4 hours and stays elevated 2-4 days
binds to actin, influencing its conformation and preventing actin-myosin interaction necessary for contraction
troponin-I
causes cardiomyopathy that develops in teen years
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
source of carbons of cholesterol
acetyl-CoA
sources of acetyl-CoA
beta oxidation of FA
oxidation of ketogenic amino acids
pyruvate dehydrogenase reaction
Where is cholesterol synthesized?
cytosol
How many NADPH are needed for the reduction of HMG-CoA?
2
How many ATP are required to transfer phosphate groups to mevalonate in isoprene formation?
3
In formation of the squalene epoxide, what other reactants are required?
O2 -> formation of the epoxide
NADPH x 2-> forms water with remaining O atom
What is the product of cyclization of squalene?
lanosterol
Cholesterol is excreted from the hepatocyte in 3 forms:
- cholesterol esters
- bile salts
- bile acids
Cholesterol is packaged into what in the intestine?
chylomicrons
Cholesterol is packaged into what in the liver?
VLDL
note: VLDL is metabolized to IDL and then to LDL
major function of HDL. Why is this important?
transport of cholesterol back to the liver -> reverse cholesterol transport
-reduces the availability of LDL for macrophages to scavenge
hormones synthesized from cholesterol
aldosterone
cortisol
sex hormones
importance of ApoCII
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
HDL is produced by
- liver with several apoproteins
- budding of apoproteins from chylomicrons and VLDL as lipolipase digests them
- free ApoI which acquires cholesterol and phospholipids from other lipoproteins and cell membranes
proteins the LDL receptor recognizes
- ApoB100
- ApoE
allows it to bind VLDL, IDL, chylomicron remnants and LDL
What causes formation of homocysteine?
mutated cystathionine beta-synthase
deficiency in vitamin B6
Elevated homocysteine in the blood (homocystinemia) promotes thrombosis
phagocytosis of LDL is accelerated by
oxidative modification of ApoB
what protein is in VLDL, LDL and IDL?
apoB100
What protein is associated with HDL?
apoA
What is the primary goal in management of patients with metabolic syndrome?
reduction of risk of clinical atherosclerosis
3 major risk factors of metabolic syndrome
- elevated LDL
- HTN
- elevated fasting glucose
How does a statin decrease LDL?
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
How does fibric acid derivative improve lipid profiles?
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.
How do cholestyramine, colestipol and colesevelam decrease LDL?
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
How does ezetimibe improve cholesterol?
inhibits cholesterol absorption from the jejunum
usually used in conjunction with a statin
How does niacin improve cholesterol?
- 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)
