Medical Physiology Block 6 Week 3 Flashcards
Describe glycolysis. What are the regulated steps?
glycolysis is a cytoplasmic pathway used by all cells to generate energy from glucose. One glucose molecule is converted into 2 pyruvate molecules, generating a net of 2 ATPs by substrate-level phosphorylation, and 2 NADHs; regulated step 1: glucose to G-6-P (enzyme is hexokinase in most tissues (low Km and negative feedback inhibition) and glucokinase (induced by insulin in the liver (high Km and no negative feedback); regulated step 2: F-6-P to F-1,6-BP (enzyme is phosphofructokinase-1 (rate limiting step upregulated by AMP, F-2,6-BP and downregulated by ATP and citrate); regulated step 3: conversion of phosphoenolpyruvate into pyruvate (enzyme pyruvate kinase (positive feedback from F-1,6-BP and negative feedback from ATP and alanine)
Which enzyme (not part of glycolysis cycle) upregulates glycolysis and decreases gluconeogensis? What is the product? What regulates the enzyme?
phosphofructokinase-2; fructose-2,6-bisphosphate; upregulated by insulin and downregulated by glucagon
What is the role of insulin on striated muscle?
glut 4 transporter insertion into the plasma membrane
Describe the role of thiamine, FAD, NAD, MG + 2 in the glycolytic pathway and explain which reactions require these cofactors
Dehydrogenase: oxidation of the substrate via transfer of (one or more) hydride ions (H”) to an electron acceptor, often NAD+ or FAD; ATP must be bound to a magnesium ion to biologically active; thiamine is a crucial component in the conversion of pyruvate to acetyl coA (aerobic)
Compare and contrast the hormonal regulation of glycolysis in the liver for a person who has fasted overnight and for a person who has just eaten a piece of cheesecake. Specifically focus on the regulated steps in the glycolytic pathway.
in the fed state, insulin and glucose activate glycolysis glycogenesis; in the fasted state, glucagon increases intracellular cAMP which activates PKA; decreases hexokinase and pyruvate kinase; stimulates glycogenolysis; also decreases activity of phosphofructokinase-2
Compare and contrast the regulation of the glycolytic pathway in the muscle and liver.
in the fed state, regulation of muscle and liver is by insulin; during exercise, the muscle does not respond to glucagon signaling and uses glucose from the blood and from its own glycogen stores for energy; PFK-2 and pyruvate kinase have no site for PKA phosphorylation (promoting glycolysis); PFK-2 is activated by AMP kinase (through increases in AMP)
Can exercise recruit GLUT4 to the plasma membrane?
Yes
Do epinephrine and glucagon have the same effects on the liver?
Yes
Discuss the role of the 2 different mitochondrial shuttles during glycolysis.
glycerol-phosphate shuttle: hydrogens and electrons are transferred from NADH to glycerol phosphate which can diffuse through the membrane into the mitochondria. Inside the mitochondria, glycerol phosphate reacts with FAD coenzyme in enzyme complex 2 in the electron transport chain to make dihydroxyacetone phosphate which in turn diffuses back to the cytoplasm to complete the cycle.
malate-aspartate shuttle: NADH is used to reduce oxaloacetate (addition of hydrogens) to malate; malate is transported across the mitochondrial membrane (in exchange for alpha ketoglutarate); in the matrix, malate is oxidized to oxaloacetate (NAD is reduced to NADH again); oxaloacetate is converted in aspartate and transported out of the mitochondria (in exchange for glutamate); aspartate regenerates oxaloacetate
Why are shuttles needed? which shuttle is used in which cell types?
mitochondrial membrane is impermeable to NADH; glycerol phosphate shuttle in brain and muscle; malate-aspartate shuttle in heart and liver
Describe the role of amino acids in the regulation of blood glucose during fasting.
During fasting, amino acids from the muscle are converted to alanine and glutamine. Alanine is converted to glucose in the liver, while glutamine is converted to ammonia and glucose in the kidney.
Describe the role of fatty acids in the regulation of blood glucose during fasting.
The decline in [insulin] and the ensuing lipolysis are sufficient to supply FAs to extracerebral tissues (e.g., muscle, heart, liver) for fuel and glycerol to the liver for gluconeogenesis.
Describe how diabetes and starvation alter ketone body urinary urea nitrogen levels.
The kidney uses the carbon skeleton of glutamine for renal gluconeogenesis and converts the amino group to ammonia, which it excretes. This ammonia excretion is particularly important in maintaining body acid-base balance during fasting. The dependence of gluconeogenesis on proteolysis is reflected by an increase in urinary nitrogen excretion in the early phase of starvation.
Compare and contrast inter-organ relationships between muscle, liver and brain in the adaption to prolonged fasting.
CNS cannot make a complete transition to ketone utilization (still requires some glucose); Cardiac myocytes preferentially catabolize fatty acids in all metabolic contexts except starvation (switch to ketone bodies); liver uses fatty acids; red blood cells and renal medulla uses glucose
Describe the phases of glucose homeostasis in humans.
Fed state: An increase in glucose and insulin activates glucokinase in the liver (is not inhibited by its product G-6-P Fasted state (glucagon signaling): increased glycogenolysis and beta oxidation Early starved state: glycogen depleted; protein breakdown; TAG hydrolysis; some production of ketone bodies Late starved state: protein breakdown slows down; TAG hydrolysis increases; production of ketone bodies
Describe the structure of fatty acids and triglycerides.
Hydrophobic tail (hydrocarbon chain) and hydrophilic head (carboxyl group); three fatty acid esterified to glycerol
Describe the fluxes of TGs and fatty acids between organs in the fed, fasted, and starved dietary states and explain the physical form in which transport between organs occurs.
Fed state: fatty acids from GI tract and fatty acids produced in the liver are esterified to glycerol-6-phosphate and transported as either chylomicrons or VLDL to adipose tissue for storage
fasted and starved state: trigylcerides are broken down and unesterified fatty acids are transported through albumin to the liver for beta oxidation or formation of ketone bodies
Name the different lipases. What is their location and function?
lipoprotein lipase: found in endothelium (free fatty acids are transported into muscle and adipose tissue); induced by insulin
hormone-sensitive lipase: found in adipose tissue (responds to phosphorylation via glucagon signaling); hydrolyzes the ester bonds at C1 or C3, liberating one FA, leaving a di-acyl glycerol (DAG) comprising the glycerol backbone with two remaining FA attached.
di-acylglycerol lipase removes a second FA, leaving mono-acylglycerol (MAG). Mono-acyl glycerol lipase then cleaves off the remaining FA, freeing glycerol
Explain how glycerol from TG breakdown is utilized.
Can be used in glycolysis or transported into the blood to the liver, where it can be used for either glycolysis or gluconeogenesis
List the major lipoproteins that transport TG through the blood. Describe the sites of synthesis and secretion of these lipoproteins and their sites of utilization.
chylomicrons: transport dietary TAGs and cholesterol from intestine to tissues (apoB-48, apoC-II, apoE); uptake by liver
VLDL: transports TAGs from liver to tissues (apoB-100, apoC-II, apoE)
LDL: deliver cholesterol into cells (apoB-100)
IDL (VLDL remnants): picks up cholesterol from HDL (apoE); taken up by liver
HDL: picks up cholesterol accumulating in blood vessels and delivers cholesterol to liver through scavenger receptor (also shuttles apoC-II and apoE in blood) (apoA-1)
What is a cofactor for lipoprotein lipase?
apoC-II
Describe the reaction of fatty acid activation in the cytosol.
FA must be linked to CoA in order to undergo lipogenesis. Fatty acyl CoA synthetase performs this reaction; The three activated FA are esterified to glycerol-3-phosphate in stages.
Describe the carnitine shuttle. Why is it important?
Acyl group is transferred from CoA to carnitine by carnitine palmitoyltransferase (CPT I) in the mitochondrial outer membrane; Acylcarnitine is transported across
the membrane by acylcarnitine/carnitine translocase (localized in the mitochondrial inner membrane) into the mitochondrial matrix; The acyl group is transferred back to CoA by carnitine palmitoyltransferase II in the matrix; Carnitine is returned to cytosolic side in exchange for another acylcarnitine
Mitochondrial inner membrane is impermeable to acyl-CoAs (activated fatty acids)
Describe beta oxidation.
takes place in the mitochondria and involves oxidative removal of 2 carbons per cycle to yield 1 NADH, 1 FADH2, and 1 acetyl-coA (oxidation, hydration, formation of ketone, thiolase)
