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1. Outline the role of the liver in sugar metabolism and the fate of glucose-6-phosphate in various pathways.

During the fed state, the liver absorbs glucose (60%) and converts it to pyruvate for use in the TAC cycle, as well as storing additional energy as glycogen. In the immediate fasting state, the liver with break down glycogen and push it into the blood stream for use by other cells. In a prolonged fasting state, the liver will begin to synthesize sugar via gluconeogenesis for use in other cells. Glucose-6-phosphate can be used to form glycogen in the fed state, and can be pushed into glycolysis in the fasting state.



2. Identify the fates of NADH, in shuttles and lactate formation, during aerobic and anaerobic glycolysis.

During aerobic glycolysis, NADH is shuttled into the mitochondria via the malate-aspartate shuttle (3 ATP produced) or the glycerol-phosphate shuttle (converts FAD to FADH2, so there are 2 ATP produced) to be used in the electron transport chain for the production of ATP. During anaerobic glycolysis, NAD+ must be regenerated in order for glycolysis to continue, so pyruvate is converted to lactate, using NADH as a cofactor, thus regenerated NAD+.



3. Define the Cori Cycle and describe its role during anaerobic muscle metabolism.

During periods of intense exercise, NADH levels begin to rise, so pyruvate is converted to lactate to restore levels of NAD+. The lactate then spills into the bloodstream, is taken up by the liver, and is converted back into pyruvate. Via gluconeogenesis, pyruvate is converted into glucose, which is then released into the blood for use by muscle cells.



4. Identify how lactate is formed.

In anaerobic metabolism (that is, in absence of oxygen), pyruvate is formed as normal in the glycolysis pathway. With the help of NADH, pyruvate is then converted to lactate as a way to regenerate NAD+ via lactate dehydrogenase.



5. Define the anaerobic threshold.

At some point, oxidative phosphorylation cannot keep up with the demands of the cell, so the cell enters anaerobic metabolism, creating lactate from pyruvate. The point at which more lactate is produced than can be metabolized is the anaerobic threshold, and results in lactic acid entering the blood and causing lactic acidosis.



6. Explain how lactate can be used as fuel in the heart and the clinical significance of LDH1 in the diagnosis of myocardial infarction.

When the ratio of NADH/NAD+ is lower than exercising muscle, the heart can reform pyruvate for use in the TAC cycle. In the heart, LDH1 is less inhibited by pyruvate and has a slower turnover of pyruvate to lactate, so lactate → pyruvate may be favored. Thus, high levels of LDH1 (compared to other LDH isoforms) are found in the blood 48 hours after myocardial infarction.




7. Outline how and in which organs lactate enters the gluconeogenic pathway.

In the liver and the kidney, lactate is converted back into pyruvate. Pyruvate is then converted into oxaloacetate, which is then converted to phospho-enol-pyruvate, which is pushed through the gluconeogenesis pathway to produce glucose-6-phosphate. This can be converted to glucose only in the liver and kidney, not the muscles.



8. Identify the causes of lactic acidosis.

When cells cannot metabolize lactate any longer, it spills into the bloodstream. In large quantities, this results in a lowering of the blood pH, which is referred to as lactic acidosis. This can result from heat stroke (blood pH is low, temperature rises), malignant hyperthermia (uncontrolled muscle contractions during anesthesia; defect is unregulated calcium pumping in response to a variety of agents), impaired electron transport (such as CN poisoning, anemia, anoxic cardiovascular shock, anesthesia, ethanol intoxication, etc), pyruvate dehydrogenase deficiency (congenital lactic acidosis), or collapse of the circulatory system (as in myocardial infarction, embolism, excessive hemorrhage, shock).



9. List the basic steps in alcohol metabolism.

Ethanol + NAD+ → Acetaldehyde + NADH + H+

Acetaldehyde → → Acetate (goes to skeletal muscles to be activated to acetyl-CoA for use in the TCA cycle)

Pyruvate + NADH → Lactate + NAD+



10. Explain how alcohol influences lactate metabolism and gluconeogenesis.

Ethanol is metabolized to acetylaldehyde and then to acetate, which results in a significant increase in cytoplasmic NADH in the liver, which favors the reduction of pyruvate to lactate. This in turn results in a decreased synthesis of glucose and potentially to hypoglycemia. People who are malnourished have depleted glycogen stores. The accumulation of lactate can cause lactic acidosis (usually mild).



11. Explain why children are particularly susceptible to alcohol-induced hypoglycemia.

Children are particularly dependent on gluconeogenesis when fasting, so ingestion of alcohol may produce severe hypoglycemia.



12. Describe differences in metabolic regulation between skeletal muscle and liver, including specific tissue responses and hormonal responses.

Skeletal muscle can either utilize glucose in glycolysis or, in cases of excess glucose, can produce glycogen as a temporary store. The user of one pathway or the other will depend on the current energy needs of the cell when it has access to glucose. If the cell is undergoing anaerobic metabolism, it will produce pyruvate for the liver to convert back to glucose.

The action of liver largely depends on the needs of the rest of the body. When blood glucose levels are high, glucose will be taken up and used directly for glycolysis, as well as stored as glycogen. In the fasting state, the liver will gain its energy by other means and will produce glucose for the other cells in the body. This is regulated largely by the action of insulin or glucagon, but also the availability of the substrates in the blood.

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