IL: Metabolic Effects of Ethanol Consumption (Exam II) Flashcards
Review: What is true about the affinity of an enzyme for its substrate if the Km is said to be low?
Review: Km is that concentration of substrate that gives a reaction velocity that is ½ Vmax; therefore, a low Km indicates that the concentration of substrate required to achieve Vmax is low, i.e. the affinity of the enzyme for the substrate is high.
What does chronic ingestion of ETOH cause?
The metabolism of ETOH to acetate increases the NADH to NAD+ ratio in hepatocytes. The rise in NADH has several important consequences, both acute and chronic. In fasting individuals, an acute effect is hypoglycemia. With chronic ingestion of ETOH, fatty liver is seen.
What effect does the rise in NADH/NAD+
have on pyruvate metabolism? Review: How might this effect relate to the advice that individuals with gout decrease their consumption of ETOH?
A rise in the NADH to NAD+ ratio favors reduction of pyruvate to lactate via lactate dehydrogenase. Review: Lactate promotes renal reabsorption of urate and thus decreases its excretion leading to hyperuricemia
How and where does a rise in mitochondrial NADH/NAD+ affect the TCA cycle?
A rise in NADH/NAD+ in mitochondria would shift oxaloacetate to malate, decreasing the availability of oxaloacetate. High NADH/NAD+ would also inhibit the isocitrate dehydrogenase step
What effect should the rise in NADH/NAD+ have on mitochondrial β-oxidation?
NAD+ is required for the second dehydrogenase reaction in fatty acid β-oxidation, and a rise in NADH/NAD+ decreases availability of the oxidized form of the coenzyme-cosubstrate, decreasing fatty acid oxidation
Explain the hypoglycemia seen with ETOH consumption
Decreased availability of the gluconeogenic precursors, pyruvate and oxaloacetate, decreases the ability of the liver to perform gluconeogenesis. In addition, decreased fatty acid oxidation increases dependence on glucose while limiting ATP (GTP)-dependent gluconeogenesis.
What effect does the rise in NADH/NAD+ have on glycolysis? What step is affected? What metabolite
accumulates? How does this influence TAG synthesis?
Glycolysis requires NAD+, so decreased availability of NAD+ as a result of a rise in NADH/NAD+ will inhibit glycolysis at the glyceraldehyde 3-phosphate dehydrogenase step.
Glyceraldehyde 3-P will accumulate. Glyceraldehyde 3-P can be converted to glycerol 3- phosphate: aldehyde to DHAP (triose phosphate isomerase), DHAP to glycerol 3-phosphate (glycerol 3-phosphate dehydrogenase + NADH).
The glycerol 3-P provides the three-carbon
backbone of TAG synthesis, so TAG synthesis will increase.
TAG synthesis requires not only the three carbon backbone, glycerol 3-phosphate, but also availability of
fatty acids. ETOH has been shown to increase lipolysis from adipose, and to inhibit fatty acid oxidation. How might increased adipose lipolysis coupled with decreased fatty acid oxidation in liver contribute to
increased hepatic TAG synthesis?
Lipolysis in adipose tissue results in free fatty acids being made available to liver; however, oxidation of these fatty acids is decreased because the NADH/NAD+ ratio is increased. The fatty acids, then, get esterified to glycerol 3-P (now plentiful), forming TAG.
The shift from oxaloacetate to malate as a consequence of the rise in NADH/NAD+ in liver not only results in
hypoglycemia but also in decreased oxidation of acetyl CoA in liver.
How does the decreased oxidation of acetyl CoA contribute to the ketoacidosis (alcoholic ketoacidosis or
AKA) seen with binge drinking in chronic alcoholics? Which ketone body would be most plentiful? Would
you expect the anion gap to be elevated?
Acetyl CoA is the substrate for synthesis of the ketone bodies (acetoacetate and β-hydroxybutyrate) in liver mitochondria. Since the rise in NADH/NAD+ shifts OAA to malate, acetyl CoA is made available for ketone body synthesis rather than being oxidized to 2CO2. β-hydroxybutyrate, because the increased NADH/NAD+ ratio favors reduction of acetoacetate.
Yes, due to increased production of nonvolatile organic acids.
Chronic consumption of ETOH results in thiamine (vitamin B1) deficiency, both because of inadequate consumption and decreased uptake in the intestine.
How might thiamine deficiency affect aerobic glucose oxidation?
Thiamine is converted to thiamine pyrophosphate (TPP). TPP is required by the transketolase of the pentose phosphate pathway, by E1 of PDH complex, and by E1 of the α-ketoglutarate dehydrogenase complex of the TCA cycle. ETOH-induced thiamine deficiency, then, should decrease aerobic glucose oxidation. [Note: Branched-chain keto acid dehydrogenase also requires TPP for its E1.]
ETOH is oxidized to acetaldehyde by hepatic ADH as NAD+ is reduced to NADH. The rise in NADH results in
- decreased gluconeogenesis
- increased ketogenesis
- increased lipogenesis
Why does ethanol cause decrease gluconeogenesis?
Rise in NADH shifts pyruvate to lactate and OAA to malate, drecreasing the availability of these gluconeogenic substrates.
Rise in NADH slows FA oxidation at the 2nd dehydrogenation rx (NADH is a product) decreasing the ATP needed for gluconeogenesis.
How does ethanol cause ketogenesis?
Decrease in OAA shifts acetyl CoA from the TCA cycle to ketogenesis, with β-hydroxybutyrate predominating due to the high NADH/NAD+ ratio.
How does ethanol cause increased lipogenesis?
NADH inhibits glycolysis at the glyceraldehyde 3-phosphate dehydrogenase rx. Glyceraldehyde 3-phosphate accumulates, is converted to DHAP and then
to glycerol 3-phosphate, which is used in TAG synthesis.
ETOH favors lipolysis in adipose, generating FA. However, the oxidation of FA is decreased and they instead are esterified to the glycerol backbone, forming TAG
Fatty liver disease due to ethanol consumption
In liver under these conditions of increased lipogenesis and ketogenesis and decreased gluconeogenesis, packaging of TAG in VLDL and/or the secretion of VLDL is impaired. This results in alcoholic fatty liver disease.
