Biochemistry of The Fed or Absorptive State - Feb 20 (10-11am) - Dr K

Match the following enzymes which are active or inactive in their dephosphorylated state: - Enzymes that are inactive in their dephosphorylated state - Enzymes that are active in their dephosphorylated state 1st choice Glycogen synthase, phosphofructokinase-2, Acetyl CoA carboxylase, pyruvate kinase and pyruvate dehydrogenase 2nd choice Glycogen phosphorylase, Hormone sensitive lipase

A. Enzymes that are active in their dephosphorylated state 1. Glycogen synthase, phosphofructokinase-2, Acetyl CoA carboxylase, pyruvate kinase and pyruvate dehydrogenase B. Enzymes that are inactive in their dephosphorylated state 2. Glycogen phosphorylase, Hormone sensitive lipase

Match the following - Glucagon domination in fasted state increases: - Insulin domination in the fed state increases: 1st choice Glucose oxidation, Glycogen synthesis, Fat synthesis, Protein synthesis 2nd choice Glycogenolysis, Gluconeogenesis, Ketogenesis

A. Insulin domination in the fed state increases: 1. Glucose oxidation, Glycogen synthesis, Fat synthesis, Protein synthesis B. Glucagon domination in fasted state increases: 2. Glycogenolysis, Gluconeogenesis, Ketogenesis

In studies with a particular cell line in culture you discover that the rate of mitochondrial fatty acid oxidation increases when the cells are stimulated to increase their rate of de novo fatty acid synthesis. This observation is quite unexpected since these 2 processes do not normally coincide. Which of the following enzymes involved in fatty acid synthesis is most likely to be altered thus, allowing for fat oxidation to be enhanced along with an increase in fat synthesis? A. Acetyl-CoA Carboxylase B. ATP-citrate lyase C. Fatty acid synthase D. Malic enzyme E. Steroyl-CoA desaturase

Acetyl-CoA Carboxylase During fatty acid synthesis the malonyl-CoA produced from acetyl-CoA carboxylase 2 (ACC2) directly interacts with carnitine palmitoyltransferase I (CPT I) at the outer mitochondrial membrane to prevent fatty acyl-CoA movement into the mitochondria. A defect in ACC2 activity would therefore lead to reduced inhibition of regulated mitochondrial transport of fatty acyl-CoA resulting in increased fat oxidation from the newly synthesized fatty acids.

___ cells are exceptionally dependent on glucose for energy because it is the only fuel molecule that can cross the blood brain barrier. Consequently, during periods of starvation (more than 2 weeks), ___ cells obtain their supply of glucose from that which is generated via gluconeogenesis in the liver. Under extreme conditions of starvation, the ___ can utilize ketone bodies as fuel. The ___ exclusively uses glucose as a fuel (GLUT-1 of the BBB is insulin independent), completely oxidizing ~140 g/day to carbon dioxide and water. Because the ___ contains no significant stores of glycogen, it is completely dependent on the availability of blood glucose. [Note: If blood glucose levels fall to <50 mg/dl (normal fasted blood glucose is 70-99 mg/dI), the cerebral function is impaired.

Brain

As the attending physician in the ER you are treating a 29-year-old woman brought in by her husband. He tells you that she has complained of breathing difficulty and has been nauseous and vomiting for the past 4 hours. He also reports that she has been using insulin for the past 8 years to treat her Type 1 diabetes. She indicates that she has not given herself an injection of insulin for the past 24 hours. Her pulse is 100/min, and respirations are 30/min. Physical examination indicates lethargy, dehydration, and deep respirations. Blood work show hyperglycemia and metabolic acidosis. Which of the following best describes the current activity of the metabolic pathways in this woman liver? Gluconeogenesis, Glycogen Synthesis, Fatty Acid Oxidation, Glycolysis A. Increased Increased Increased decreased B. Increased Increased decreased decreased C. Increased decreased increased decreased D. Decreased Increased Increased increased E. Decreased decreased decreased decreased A. A B. B C. C D. D E. E

C Associated with insulin deficiency in Type 1 diabetes is uncontrolled glucagon secretion. In the absence of injected insulin in this patient, she will have exacerbated responses to the increased glucagon. These responses will include increased hepatic gluconeogenesis and increased glycogen breakdown. In addition, the rate of glucose oxidation will be reduced and fatty acid oxidation will be increased. All of these effects are exerted via glucagon-mediated increases in the activity of PKA.

In the fed state, dietary triglycerols→free fatty acids by pancreatic lipase after TG's are emulsified by bile salts. The triacylglycerols are packaged with proteins, phospholipids, cholesterol, and other compounds into the lipoprotein complexes known as ___ which are secreted into the lymph and ultimately enter the bloodstream. Dietary proteins are digested to amino acids, which are absorbed into the blood. In cells, the amino acids are converted to proteins or used to make various nitrogen-containing compounds such as neurotransmitters and heme. The carbon skeleton may also be oxidized for energy directly, or be converted to glucose.

Chylomicrons or VLDL

Acetyl COA Carboxylase (ACC) is a *rate-limiting enzyme of fatty acid (palmitoyl-CoA) synthesis* will be activated allosterically or feed-forwardly by ___ and inhibited by Palmitoyl CoA in a feedback manner.

Citrate

The activity of many enzymes is regulated by the addition (via kinases) or removal (via phosphatases) of phosphate groups from specific serine, threonine, or tyrosine residues of the protein. In the absorptive state, most of the covalently regulated enzymes are in the ___ form and are active. Three exceptions are glycogen phosphorylase kinase, glycogen phosphorylase, and hormone-sensitive lipase (HSL), which are inactive in their ___ form.

Dephosphorylated

___ muscles can use glucose from the blood or from their own glycogen stores, converting glucose to lactate through glycolysis or oxidizing it completely to CO2 and H2O.

Exercising skeletal

___ is the major counterregulatory hormone. The term "counterregulatory" means that its actions are generally opposed to those of insulin (contra insular). The major action of this hormone is to mobilize fuel reserves by stimulating glycogenolysis and gluconeogenesis. These actions ensure that glucose will be available to glucose-dependent tissues between meals. Whereas, ___ is the major anabolic hormone. It promotes the storage of nutrients as glycogen in liver and muscle and as triacylglycerols in adipose tissue. It also stimulates the synthesis of proteins in tissues such as muscle. At the same time, it acts to inhibit fuel mobilization.

Glucagon; insulin

Conversely, under fed conditions, insulin serves to lower blood glucose levels by promoting the synthesis of ___ (to store glucose), stimulating glycolysis (to catabolize glucose), and inhibiting the activity or synthesis of enzymes involved in gluconeogenesis. A deficiency in insulin production (type 1 diabetes) or insensitivity to insulin (type 2 diabetes) results in elevated blood glucose levels.

Glycogen

Which one of the following enzymes is phosphorylated and active in an individual who has been fasting for 12 hours? A. Arginase B. Carnitine palmitoyltransferase-I C. Fatty acid synthase D. Glycogen synthase E. Hormone-sensitive lipase

Hormone-sensitive lipase Hormone-sensitive lipase of adipocytes is phosphorylated and activated by protein kinase A in response to epinephrine. Choices A, B, C, and F are not regulated covalently. Choices D and G are regulated covalently but are inactive if phosphorylated.

A marathon runner is training for a race. Two days before the race, the runner exhausts her glycogen stores through an extensive training session and then goes out and eats a large helping of pasta, a process known as "carb loading," which is designed to do which ONE of the following? A. To induce the release of glucagon from the pancreas B. To release insulin to stimulate glucose entry into the nervous system C. To stimulate glycogen synthesis in liver and muscles D. To stimulate the oxidation of glucose to carbon dioxide in the muscle E. To stimulate red blood cell production of carbon dioxide from glucose

To stimulate glycogen synthesis in liver and muscles After a high-carbohydrate meal, glucose is the major fuel for most tissues, including skeletal muscle, adipose tissue, and liver. The increase in blood glucose levels stimulates the release of insulin, not glucagon. Insulin stimulates the transport of glucose in skeletal muscle and adipose tissue, not brain. Liver, not skeletal muscle, converts glucose to fatty acids. Although the red blood cell uses glucose as its only fuel at all times, it generates ATP from the conversion of glucose to lactate, not CO2. When the muscle totally depletes its glycogen stores through exercise and then a meal containing carbohydrate is ingested, the muscle and liver will synthesize glycogen to replete those stores; in the case of muscle, the amount of glycogen synthesized is greater than normal, leading to higher-than-normal glycogen stores in the muscle and an advantage for the muscle during exercise.

When cells acquire sufficient energy such that the rate of flux through the TCA cycle declines, excess acetyl-CoA that cannot be oxidized is predominantly converted into fat. In order for the carbons in mitochondrial acetyl-CoA to serve as a precursor for fat synthesis, they must be delivered to the cytosol. Which of the following represents the molecule used to transport acetyl-CoA to the cytosol? A. acetyl-CoA B. carnitine C. citrate D. β-Hydroxybutyrate E. pyruvate

citrate Acetyl-CoA cannot freely diffuse across the membranes of the mitochondria, nor is there a transport mechanism to move the molecule to the cytosol. This ensures that all acetyl-CoA generated by PDH or fat oxidation will be used for energy production. However, as cellular energy demand falls, carbon atoms can be diverted into storage molecules such as glycogen and fatty acids. To move acetyl-CoA out of the mitochondria to the cytosol, it must first be converted to citrate, which can be transported by the TCA transport system.

When glucose deficiency occurs (e.g., after 4 hours of having carbohydrate meal), the pancreas releases the peptide hormone glucagon. Glucagon then elevates blood glucose levels by promoting the breakdown of glycogen in the liver and inhibiting glycogen synthesis. Similarly, epinephrine stimulates the breakdown of glycogen by promoting glucagon secretion. If the glycogen stores have been depleted, then glucagon eventually stimulates ___ by inducing the transcription of enzymes involved in this glucose-producing pathway. In general pancreatic α-cells produce glucagon.

gluconeogenesis

Which of the following enzymes is activated by dephosphorylation? A. glucose 6-phosphatase B. UDP-glucose pyrophosphorylase C. glycogen phosphorylase D. glycogen synthase E. phosphoglucomutase

glycogen synthase The activity of glycogen synthase is inhibited when the enzyme undergoes phosphorylation. There are a number of kinases that target this enzyme for inhibition including glycogen synthase-phosphorylase kinase, PKA, PKC, and GSK-3. Thus, removal of the phosphate added by any of these enzymes would result in increased glycogen synthase activity.

Which of the following metabolic processes is promoted by insulin? A. catabolism of muscle protein B. fatty acid oxidation C. gluconeogenesis D. glycogenesis E. lipolysis

glycogenesis The primary hormonal effects of insulin are the conversion of carbon energy into storage molecules. These actions include the incorporation of glucose into glycogen and the activation of lipogenesis pathways to increase the synthesis of triglycerides. Catabolic processes are inhibited in response to insulin actions.

A normal subject fasts overnight. In the morning serum glucose concentrations are within the reference range. Which of the following is the best explanation for this result? A. hepatic gluconeogenesis in response to insulin B. hepatic gluconeogenesis in response to glucagon C. hepatic ketogenesis in response to glucagon D. muscle glycogenolysis in response to glucagon E. muscle ketogenesis in response to insulin

hepatic gluconeogenesis in response to glucagon

You are studying the effects of the addition of a novel compound to the chow of laboratory animals on the overall rate of flux through glycolysis. You discover that when the animals consume the compound containing chow, there is an increase in glycolytic flux to pyruvate. Examination of serum hormone levels in these animals indicates a change in the ratios of several key regulators of glucose homeostasis. The consumption of the test compound most likely causes an increase in which of the following hormone ratios, thus best explaining the observed changes in the rate of glycolysis? A. cortisol to insulin B. epinephrine to glucagon C. glucagon to insulin D. insulin to glucagon E. insulin to cortisol

insulin to glucagon As the level of insulin rises, there will be a concomitant increase in the activity of phosphodiesterase within responsive cells, such as the liver. The phosphodiesterase will hydrolyze cAMP leading to reduced activity of PKA. As the activity of PKA falls, the level of phosphorylation of 6-phosphofructo-2-kinase, PFK2 will fall which reduces its phosphatase activity. When functioning as a phosphatase, PFK2 hydrolyzes fructose-2,6-bisphosphate (F2,6BP) to fructose 6-phosphate. When PFK2 is not phosphorylated, it acts as a kinase and will, therefore lead to increased levels of F2,6BP. Conversely, as the level of glucagon increases, the activity of PKA increases leading to increased phosphorylation of PFK2. This in turn results in decreased F2,6BP levels due to the phosphatase activity of PFK2.

Insulin inhibits glucose mobilization by down regulation of what biochemical pathways?___, ___ and ___

↓glycogenolysis ↓gluconeogenesis ↓lipolysis