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7 Cards in this Set
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Discuss the regulation of glycolysis in skeletal muscle
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There are three irreversible enzymes in glycolysis: hexokinase/glucokinase, PFK-1, pyruvate kinase. Hexokinase is regulated allosterically; it is inhibited by its product Glc-6-P. It is not an important regulatory site because it is a branch point for other metabolic reactions (Glc-6-P can also feed into glycogenesis and the PPP). PKF-1 is inhibited by ATP, a decrease pH, but activated by AMP and phosphorylated PFK-2 (via Fructose-2,6-BisP). Pyruvate kinase (tetramer, M4/L4) is the most important regulatory enzyme and controls pyruvate production. It is inhibited by alanine (synthesized from pyruvate) and ATP (allosteric), but activated by Fructose-2,6-BisP.
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Explain the energetic advantages of using glycogen as a source of glucose
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Glycogen is stored in the muscle and liver; liver glycogenolysis is not inhibited by low pH because lactate does not accumulate in the liver. Insulin activates glycolysis in the liver, stimulating the dephosphorylation of PFK-2; PFK-2 then produces Fructose-2,6-BisP which activates glycolysis (via PFK-1) and inhibits fructose-1,6-bisphosphatase (gluconeogenesis). Glucokinase has a higher Km than hexokinase so that neurons/myocytes can preferentially use blood glucose. Glucagon stimulates cAMP production thereby inhibiting glycolysis and stimulating gluconeogenesis. The liver, capable of performing gluconeogenesis, uses the remnants of the glycolytic pathway.
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Discuss the regulation of gluconeogenesis and glycolysis in liver and how they are linked
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Gluconeogensis is indirectly influenced by the concentration of lactate and other glucose precursors in the blood and is subject to hormonal regulation. Insulin stimulates glycogenolysis, gluconeogenesis, and ketogenesis; Glucagon and epinepharine (trumps insulin by elevating cAMP) stimulates glycogenolysis, gluconeogenesis, and ketogenesis. Glucocorticoids (stress hormones) stimulate synthesis of gluconeogenic enzymes by influencing gene transcription. Glucagon activates F-1,6-BPase (gluconeogenesis) and inhibits PFK-1 (glycolysis), it phosphorylates pyruvate kinase (cAMP protein kinase activity inactivates enzyme), and increases transcription of PEP-carboxykinase (enzyme induction).
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Describe how, during starvation, precursors are channeled into gluconeogenesis
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Glucose → Glycogen → Gluconeogensis, NEFA (muscle/liver), lipolysis → hepatic ketogenesis
Muscle proteolysis provides the C skeleton from gluconeogenic AA for gluconeogenesis). Liver glycogen lasts 12-24 hours (depending on activity and insulin/glucagon ratio). Insulin suppresses proteolysis, thus with falling insulin levels, muscle proteolysis increases (elevated serum glutamine levels). Glucagon promotes increased hepatic alanine uptake and conversion to pyruvate. Increased lipolysis also supplies glycerol to the liver (precursor for gluconogenesis); LPLase in adipose tissue releases glycerol and NEFAs from stored TAG into the blood. NEFAs are then utilized as a major source of energy by most tissues while glycerol is phopshorylated by hepatic glycerol kinase and directed into carbohydrate metabolism. |
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Discuss the links between lipolysis, gluconeogenesis, and glycolysis, especially the role of acetyl-CoA-glucose sparing
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Hepatic acetyl-CoA (from B-oxidation) is an allosteric activator of pyruvate carboxylase (pyruvate → OAA) thus increasing gluconeogensis in addition to being an allosteric inhibitor of PDH (also inhibited by NADH produced during B-oxidation). When blood glucose levels are low (low insulin/glucagon ratio), glucose will be taken up in the blood by non-insulin dependent GLUTs; some GLUTs have a high affinity for glucose (ie: GLUT 2 brain, relies on glucose for E and NT synthesis).
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Explain the effects of high ethanol consumption of glyconeogensis
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Ethanol is ketogenic and not glucogenic. It is metabolizd by the liver and by the stomach wall/mucosal lining. Hepatic accumulation of NADH (produced by ethanol catabolism) influences hepatic LDH favoring lactate formation via the cori cycle (from pyruvate). Pyruvate is thus not used as a gluconeogenic precursor; lactate accumulates causing lacticacidemia. A high NADH/NAD+ ratio inhibits B-oxidation (product is NADH) of FA resulting in hepatic steatosis and VLDL production.
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