Handout 10: Integrative Metabolism

T

(T/F) Adipocytes do not have glycerol kinase like the liver, so G-3-P can only be produced from excess glucose by glycerol phosphate dehydrogenase.

T

(T/F) All of our cells have the same genetic information; although, the suppression of these genes varies between tissues

F (this is known as METABOLIC REGULATION) metabolic = energy (calories)

(T/F) Balancing between the need for energy and available fuels is another way of saying "Glucose Homeostasis."

T

(T/F) Brain completely oxidizes glucose to CO2 and H2O

T

(T/F) Despite the brain not oxidizing fatty acids for fuel, it still uses them for the membrane synthesis of fatty acid derivatives like phospholipids, myelin, etc.

T

(T/F) Only lipoprotein exported from the liver (7) is VLDL.

No! Only alpha-ketoacids can be used to participate in TCA and glycolysis in the liver because it lacks the enzyme beta-ketoacyl-CoA transferase. This enzyme attaches coenzyme A to beta-ketoacids

(T/F) Some fatty acids are converted to beta-ketoacids so that the liver can utilize beta-ketoacids and alpha-ketoacids for fuel

T glucose ⟶ ⟶ dihydroxyacetone phosphate ⟶ G-3-P ⟶ 2 fatty acids at R1 + R2 ⟶ ⟶ phosphatidic acid ⟶ 1,2-diacylglycerol ⟶ triacylglycerol

(T/F) The esterification of fatty acids to G-3-P proceeds the same way in adipocytes.

T

(T/F) The liver recycles metabolic fuels

cytosol; mitochondria; cytosol

In gluconeogenesis, substrates such as lactate and pyruvate are formed in the _____, then enter the _____ to yield oxaloacetate as a precursor for the synthesis of glucose in the _____.

Fatty acids and yes, they are fully oxidized, but only in the presence of oxygen.

In resting muscle, what is the major fuel source during the fed state? Is it fully oxidized?

Glycolysis: since they don't use oxygen they convert pyruvate to lactate via fermentation for producing ATP.

In the fed state, RBC only utilize what metabolic pathway for energy?

Triacylglycerol synthesis is promoted by acetyl CoA, fatty acids, and glycerol 3-P availability.

In the fed state, what stimulates the synthesis of triacylglycerol in adipocytes?

stimulates; stimulates

Insulin (inhibits/stimulates) amino acid uptake and (inhibits/stimulates) protein synthesis in skeletal muscle.

stimulates; inhibits

Insulin (inhibits/stimulates) glycogen synthesis and (inhibits/stimulates) gluconeogenesis in both liver and muscle.

stimulates

Insulin (inhibits/stimulates) the synthesis of albumin and other blood proteins in the liver.

accelerates

Insulin _____ glycolysis to increase glucose conversion to triacylglycerol, and storage of fat in adipose tissue.

glycogen synthase (+) glycogen phosphorylase (-) Overall effect, promotes the storage of excess glucose as glycogen.

Insulin activates glycogen _____ and simultaneously inactivates glycogen _____. What does this effect allow insulin to promote?

fatty acid biosynthesis (+): de novo synthesis of fatty acids from acetyl CoA in adipose tissue lipoproteins: insulin transcriptionally up-regulates lipoprotein lipase triacylglycerol biosynthesis: through the stimulation of glycolysis which supplies the glycerol; and fatty acids from both diet and de novo synthesis.

Insulin binds to GLUT4 receptors in adipose tissue and promotes _____ biosynthesis. At the same time insulin, activates the absorption of fatty acids from _____. Together this overall effect promotes the synthesis of _____.

direct

Insulin has a (direct/indirect) relationship with blood glucose levels.

carbohydrate and lipid transcriptional level and post translational level

Insulin regulates both _____ and _____ metabolism at both the _____ level and _____ level.

In the liver, glycolysis is significant only during the absorptive period following a carbohydrate-rich meal. The conversion of glucose to pyruvate is stimulated by the elevated insulin/glucagon ratio that results in increased amounts of the regulated enzymes of glycolysis: glucokinase, PFK-1, and pyruvate kinase. Additionally, PFK-1 is allosterically activated by fructose 2,6- bisphosphate generated by the active (dephosphorylated) kinase domain of bifunctional PFK-2. PK is dephosphorylated and active. Pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl CoA, is active (dephosphorylated) because pyruvate inhibits PDH kinase. The acetyl CoA either is used as a substrate for fatty acid (+ acetyl CoA carboxylase) synthesis or is oxidized for energy in the tricarboxylic acid (TCA) cycle.

Insulin stimulates the storage of energy. How does it do this in the liver?

No, abundance of GLUT2 transporters in comparison to glucose allow for the rapid uptake of blood glucose from mass-action.

Is glucose uptake in the liver the rate limiting step? Why?

No, it's actively contracting so the fatty acids must be imported quickly for energy.

Is passive diffusion sufficient enough for fatty acid import in cardiac muscle?

Yes

Is passive diffusion sufficient enough for fatty acid import in resting muscle?

left off at 14:08 recording 3 (under integrative module)

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The liver prefers generating ATP from amino acids over glucose and fats. Preference is given because amino acids and proteins have no significant storage sites, and the accumulation of nitrogenous compounds is toxic. Thus, amino acids are deaminated in the urea cycle (blue), producing alpha-keto acids. Their carbon skeletons are then converted to pyruvate (red), acetyl CoA (yellow), and TCA intermediates. They can enter the Krebs cycle for the generation of ATP to be used by the liver (catabolic process).

After a high protein meal, what is the fate that excess amino acids undergo in the liver?

Glucose and fats will be catabolized for energy production.

After a low protein meal, how does the liver produce energy?

Black pathway: glucose ⟶ G-6-P ⟶ pyruvate ⟶ acetyl-CoA ⟶ TCA ⟶ ETC ⟶ ATP

After a meal, what is the first metabolic pathway, followed by adipocytes, when glucose is the substrate?

Green pathway: glucose is used to make G-3-P This path requires the ATP synthesized by the first fate. Adipocytes cannot synthesize "de novo" triacylglycerol to be stored within them without ATP.

After a meal, what metabolic pathway is followed by adipocytes, when there is an excess of glucose and enough ATP was synthesized already?

Brain first RBC second

Are decreased glucose levels more dangerous for the brain or RBC?

No

Are ketone bodies available for the brain to use in the fed and early-fasting state?

cytosol; mitochondria

At a subcellular level, glycolysis occurs in the _____ and the kreb's cycle occurs in the _____.

blood: don't require a protein transporter because beta-ketoacids are water soluble.

Beta-keto acids produced in the liver during the fed state are secreted to the _____.

beta-keto acids (ketone bodies = common name) Top structure = Acetoacetate Bottom structure = β-hydroxybutyrate

Both of these structures are known as _____.

(1) Rate of synthesis or degradation controls the amount of enzyme. (2) Allosteric regulation in the form of feedback to activate or inactivate enzymes. (3) Covalent modifications usually via reversible phosphorylation. (4) Compartmentation secludes metabolic pathways preventing unwanted interactions between the paths. (5) Metabolic specificity is often predetermined by the needs of an organ or tissue.

Describe the common mechanisms associated with metabolic regulation.

(1) Insulin activates protein kinase cascades to stimulate glycogen synthesis in the liver and muscles, glycolysis and fatty acid synthesis, and to suppress gluconeogenesis. (2) Excess blood-glucose is removed by the liver where glucokinase converts it to glucose 6-P for glycogen synthesis (glucokinase is not inhibited by glucose 6-P). (3) Glucose binds to and allosterically inactivates glycogen phosphorylase; preventing glycogen degradation. (4) Insulin promotes entry of glucose into the adipose tissue (insulin dependent GLUT) for triacylglycerol synthesis from glycerol 3-P. (5) Insulin promotes entry of glucose and branched-chain amino acids into the muscle (insulin-dependent GLUT) for synthesis of glycogen and proteins. Insulin also inhibits protein degradation.

Describe the effects of insulin in the well-fed state after a meal.

No, the synthesis of beta-keto acids (ketone bodies) is very slow after a meal.

Does point 5 occur often, during the fed state in the liver?

In actively contracting muscle, glucose sends a signal to fatty acid translocase located in the cytosol, to insert itself into the plasma membrane. It will then transport fatty acids, acquired from plasma bound (VLDL/chylomicrons) triacylglycerol from hydrolysis by lipoprotein lipase. Allows for quick import into the cell to meet the energy

Explain the mechanism of fatty acid translocase in myocytes during the fed state:

In times when sugars are not readily available for energy production, a signal (see below) is sent to the lipid storage tissues to mobilize fats. In mammals, PKA phosphorylates perilipin 1 (PLIN1), relieving its inhibition of adipose triglyceride lipase (ATGL). PKA also phosphorylates hormone-sensitive lipase (HSL), thereby activating it, and, together with ATGL, the two proteins catalyze the breakdown of TAG from the lipid droplets to FAs. In mammals, the FAs released from the adipocytes are taken up by the body tissues for energy production. Hepatocytes also use the FAs to produce ketone bodies that are used by the brain and muscle for energy production Hydrolysis of triacylglycerols to fatty acids and glycerol is catalyzed by the hormone-sensitive lipase that is regulated through phosphorylation by protein kinase A stimulated via epinephrine receptor (GPCR). Also, occurs because insulin is no longer inhibiting HSL and glucagon stimulates it. DOES NOT OCCUR IN THE FED STATE

Explain the mobilization of fatty acids and glycerol when fuel is scarce:

pyruvate; NAD Lactate dehydrogenase

In fast contracting muscle, glucose is converted to _____, which will undergo fermentation to lactate to recover ______. This reaction is catalyzed by what enzyme?

fatty acid translocase (FAT/CD36)

Fatty acids can enter muscle via passive diffusion, but it isn't fast enough for actively contracting muscle. Thus, fatty acid transporters are used for faster uptake. What specific transporter facilitates the uptake of long chain fatty acids (16, 18, 20+ carbons) in muscle (also in adipose)?

(1) Pyruvate (2) alpha-ketoglutarate (3) oxaloacetate THESE ARE DIFFERENT FROM BETA-KETO ACIDS

Give 3 examples of alpha-keto acids derived from amino acids:

indirect

Glucagon has a (direct/indirect) relationship with blood glucose levels.

independent (because it isn't GLUT 4!!! has GLUT2 transporter)

Glucose transport into the liver is (dependent/independent) of insulin.

Dietary fats in the form of triglycerides (TAG) are broken down in the gut lumen by lipases to facilitate absorption into the epithelium. The monoglyceride (MAG) and fatty acids (FAs) are used to reform TAG (or diglyceride (DAG) and packaged into lipoprotein particles (chylomicrons), which are released into circulation and travel to the site of lipid storage (adipose tissue) if the fats are not immediately consumed for ATP production

How are dietary triacylglycerols broken down in the small intestine?

The TAG is broken down by lipoprotein lipase into glycerol and FAs that can then be taken up into the adipocytes. Fatty acids taken up by adipocytes (by the action of the lipoprotein lipase in capillary walls in adipose tissue) are activated and the resulting fatty acid-acyl CoA is transferred to glycerol 3-phosphate (which comes from glycolysis that occurs in adipocytes). These components are then used to resynthesize TAG, which is then stored in the lipid droplets.

How are dietary triacylglycerols utilized by adipocytes?

A decrease in plasma glucose concentration is the primary stimulus for glucagon release. During an overnight or prolonged fast, elevated glucagon levels prevent hypoglycemia. Glucagon secretion is significantly decreased by elevated blood glucose and by insulin.

How is glucagon release stimulated by glucose levels in pancreatic α cells?

Glucose-dependent release of insulin into blood is mediated through a rise in calcium (Ca2+) concentration in the β cell. Glucose taken into β cells by GLUT-2 is phosphorylated and metabolized, with subsequent production of ATP. ATP-sensitive potassium (K+) channels close, causing depolarization of the plasma membrane, opening of voltage-gated Ca2+ channels, and influx of Ca2+ into the cell. Ca2+ causes vesicles containing insulin to be exocytosed from the β cell.

How is insulin release stimulated by carbohydrates in pancreatic β cells?

Insulin transcriptionally up-regulates lipoprotein lipase

How is lipoprotein lipase affected by the fed state?

Phosphate group is cleaved and used to generate ATP from ADP. This process is very fast and provides the 2nd source of ATP.

How is phosphocreatine used to generate ATP within fast contracting myocytes?

Glycerol 3-phosphate accepts fatty acids in the synthesis of triacylglycerol. G-3-P is synthesized from dihydroxyacetone phosphate, which is produced in glycolysis. The reduction of DHAP to G-3-P is catalyzed by G-3-P dehydrogenase. The majority of fatty acids are provided by Chylomicrons and VLDL.

How is triacylglycerol synthesized "de novo" by adipocytes during the fed state?

esterfied

If glycerol 3-phosphate is abundant, then fatty acids are _____.

are released to blood (occurs a few hours after a meal)

If glycerol 3-phosphate is scarce, then fatty acids are _____ to the _____.

alpha-ketoacids

Illustrated are the fuels for the liver during the fed state. Which fuel is the predominant source of energy for the liver during this time?

Chylomicrons absorbed by liver contain triacylglycerol thats broken down into glycerol and fatty acids. Glycerol must be phosphorylated by glycerol kinase to become G-3-P. Thus, G-3-P is derived differently from carbohydrates and fats. One thing both macromolecules have in common, is the production of phosphatidic acid by esterifying fatty acids at positions R1 and R2 on G-3-P.

Illustrated is glycerol 3-phosphate being derived for the synthesis of triacylglycerol. Which of these paths shows how G-3-P is acquired from chylomicron remnants in the liver?

Lipogenesis: storage of fatty acids within triacylglycerols Glycolysis: upregulates glucokinase Gluconeogenesis Beta Oxidation

Illustrated is insulin upregulating the genes for what? What does it downregulate?

alpha-ketoacids cannot, but beta-ketoacids (ketone bodies) can be used during fasting just NOT DURING THE FED STATE.

Illustrated is the metabolic path for fuels used by muscle during the fed state. Can alpha-ketoacids and beta-ketoacids (ketone bodies) be used?

Brain

Illustrated is the metabolic path occurring in what organ during the fed state?

First fuel = glucose Second fuel = fatty acids

Illustrated is the metabolic pathways occurring in adipocytes in the fed state. What is their main fuel source? What do they use for fuel after glucose levels decline?

Glucose (prefers glycolysis) and it depends on the speed of contractions. If muscle contraction is slower glucose can be fully oxidized. However, when muscle contraction is fast, oxygen cannot keep up, so anaerobic fermentation will occur. In anaerobic fermentation one glucose molecule is converted to two pyruvates and fermentation follows.

In active muscle, what is the major fuel source during the fed state? Is it fully oxidized?

Glycolysis

In fast contracting muscle, does TCA or glycolysis provide faster supplies of energy from ATP?

(1) ATP (2) Phosphocreatine (phosphocreatine pool is synthesized when ATP is high and the muscle is resting by creatine kinase phosphorylating creatine; doesn't last long ~30-40 sec) (3) Glycogen (broken down to G-6-P and metabolized by glycolysis and undergoes fermentation) (4) Glucose (if insulin and glucose are present in blood) (5) Fatty acids (later into the muscle activity; deliver ATP by oxidative phosphorylation after the above fuels are exhausted)

Organize and explain, the following fuel sources in order of their utilization in fast contracting muscle: Fatty acids Phosphocreatine Glycogen Glucose ATP

specific; different

Organs and tissues have _____ functions that require _____ metabolic profiles, which requires different substrates.

Thiolase, cleaves acetoacetyl CoA into two acetyl CoA molecules. Since, acetyl CoA is what enters the TCA cycle for ATP production, the liver just exports beta-ketoacids to other tissues.

The following reaction is not carried out in the liver because it doesn't have the enzyme beta-ketoacyl-CoA transferase. This enzyme transfers coenzyme A from succinyl CoA to the beta-ketoacid. What does the thiolase enzyme after this catalyze? How does the final product generate energy?

reduction; glycerol phosphate dehydrogenase this is how glycerol is synthesized from glucose in the liver

The glycerol backbone for triacylglycerol is derived from glycolysis. Glycerol 3-phosphate is a product of the (oxidation/reduction) of dihydroxyacetone phosphate by the enzyme _____.

Phosphatidic acid is dephosphorylated by phosphatidic acid phosphatase to produce 1,2-diacylglycerol. Then, acyl transferase esterfies position R3, with an acyl group from CoA-SH producing triacylglycerol.

The liver esterfies fatty acids to produce triacylglycerol when fuels are abundant during the fed state. What are the final steps in triacylglycerol synthesis?

(1) Energy needs of the body (2) Hormones and other signaling molecules (3) Concentration of available fuels These will differ between fed, fasted, and starved states

What 3 elements determine whether a fuel is metabolized (catabolic) or stored (anabolic)?

glucose (from carbohydrate digestion); amino acids (primary organ that absorbs AA after entering blood); chylomicron remnants (fats from the triacylglycerol digestion via receptor mediated endocytosis)

What 3 macromolecules are utilized by the liver?

(1) Glycogen (2) Triacylglycerols

What are the 2 major forms of energy storage in the liver during the fed state?

glucose; acetoacetate; β-hydroxybutyrate

What are the 3 metabolic substrates used by the brain?

fatty acids, glucose, ketone bodies (beta keto acids)

What are the 3 substrates utilized by the muscle?

(1) Protein synthesis, including albumin, lipoproteins, and clotting factors (2) Synthesizes and metabolizes fats, including fatty acids and cholesterol, both of which are esterfied then packaged into VLDL for redistribution to other tissues (3) Metabolizes and stores carbohydrates for maintaining blood glucose (to be used by brain and RBC) (4) Synthesizes and secretes bile, which contains bile acids and salts for for fat and vitamin digestion (5) Elimination of toxic metabolites produced by the body (6) Detoxification by removing drugs, alcohol, and environmental toxins from the body

What are the metabolic functions of the liver?

metabolic syndrome, insulin resistance, and dyslipidemia all caused from the accumulation of lipid droplets in the plasma membrane.

What diseased states are linked to altered expression of fatty acid translocase?

Glucokinase (Km = 10mM): transcriptionally upregulated by insulin, which increases the phosphorylation of glucose (not inhibited by the product like hexokinase in other tissues)

What enzyme catalyzes the conversion of glucose ⟶ glucose 6-phosphate in the liver? How is it regulated?

Fatty acyl CoA will enter the mitochondria via the carnitine transport system. First, fatty acyl CoA is converted to acylcarnitine by carnitine acyl transferase I (bound to the outer mitochondrial membrane). Second, acylcarnitine enters the mitochondria by carnitine acyl translocase. Once in the matrix, carnitine acyl transferase II catalyzes the transfer of the acyl group back to CoA-SH, and carnitine is transported back to the cytosol by the same translocase. Finally, fatty acyl CoA can undergo beta-oxidation to ultimately generate ATP for the myocyte.

What happens after fatty acyl CoA is formed?

Glycogen is being mobilized, which is signaled by epinephrine. Glycogen stores in muscle are never used by other tissues. The stores are reserved for muscle only.

What happens during the time that ATP and phosphocreatine (first two sources) are being used as fuel by fast contracting muscle?

Oxygen is building up so that fatty acids can be oxidized for energy.

What happens during the time that ATP, phosphocreatine, and glycogen (first 3 stores) are being used as fuel by fast contracting muscle?

Fatty acyl synthase catalyzes the attachment of an acyl group from coenzyme A, forming fatty acyl coenzyme A. Also, known as fatty acid thiokinase since it catalyzes (1) a phosphorylation, (2) cleavage of AMP and formation of thioester linkage with HS-CoA.

What happens immediately after fatty acids are transported into the myocyte?

Glucose-alanine Cycle: Muscle cannot fully deaminate amino acids. So all protein broken down in muscle, must transfer the amino groups to pyruvate, which produces alanine. Alanine can then be excreted from myocytes to the liver where it can be used by other processes including gluconeogenesis. Process describes how the muscle exports nitrogen.

What happens to the alanine generated from anaerobic glycolysis in fast contracting muscle?

Increased protein synthesis: An increase in amino acid uptake and protein synthesis occurs in the absorptive period after ingestion of a meal containing protein. This synthesis replaces protein degraded since the previous meal.

What happens to the amino acids absorbed by the muscle during the fed state?

When fuel is abundant, they will not be oxidized in the mitochondria. Instead they will be esterfied and secreted, into the blood as VLDL, which is transported to adipocytes. The phospholipids and proteins are recycled; however, triacylglycerol is hydrolyzed to fatty acids and glycerol 3-phosphate by lipoprotein lipase. Then new triacylglycerol is synthesized with a different combination of fatty acids. Finally this new triacylglycerol is exported via VLDL to peripheral tissues. Cholesterol retained within the chylomicron will also be repackaged as VLDL and secreted into the blood.

What happens to the chylomicron remnants (dietary fat) absorbed by the liver during the fed state?

The Cori Cycle: Lactate is exported to the blood until it reaches the liver. Once in the liver it undergoes gluconeogenesis and produces 1 molecule of glucose from 2 molecules of lactate. The glucose is exported to the blood for use by other tissues.

What happens to the lactate generated from anaerobic glycolysis in fast contracting muscle?

insulin/glucagon ratio

What hormones regulate glucose homeostasis?

Lipid rafts: required for the cellular uptake of long-chain fatty acids. Translocase's presence is exclusive to lipid rafts.

What is fatty acid translocase's cellular localization?

Liver isn't able to export dietary lipids, causing the accumulation of VLDL and triacylglycerol. Very serious and dangerous for the liver, because the cells shrink and can't perform proper functions. Common in alcoholics

What is fatty liver?

Synthesize proteins (green) necessary for the liver and blood (anabolic process)

What is the first fate that amino acids undergo in the liver during the fed state? What stimulates it?

red pathway; stimulated by insulin dephosphorylating glycogen synthase; moreover, more glucose 6-phosphate is available which is its positive allosteric effector. glucose ⟶ glucose 6-phosphate ⟶ glycogen

What is the first metabolic pathway glucose 6-phosphate undergoes in the liver during the fed state? What stimulates it?

Proteins: practically all circulating proteins are produced by the liver.

What is the main compound synthesized by the liver?

Integrative metabolisms main goal, is to maintain constant blood glucose levels. Formally, as GLUCOSE HOMEOSTASIS

What is the main goal of metabolic regulation?

Usually is not used by the liver for energy in any significant amounts. Instead acetyl CoA is transformed into 2 other forms (fatty acids being the main thing). (1) Fatty acids synthesis (blue): acetyl CoA ⟶ fatty acids ⟶ triacylglycerol (the backbone glycerol is provided by the byproduct, glycerol 3-phosphate (G3P) from glycolysis) (2) Cholesterol (pink): acetyl CoA ⟶ cholesterol

What is the major fate of acetyl CoA produced by the liver in the fed state?

Glucose: Imported into the cell via GLUT4 (insulin dependent). Used to generate enough ATP for cellular functions. Functions like synthesis of fatty acids and esterification of glycerol and fatty acids.

What is the major fuel source for adipocytes during the fed state?

They transport oxygen to other tissues for oxidative phosphorylation. However, they don't use oxygen themselves, because they lack mitochondria.

What is the major role of erythrocytes for integrating metabolism?

adipose tissue; it's packaged into VLDL and transported in the blood (minor tissue = muscle)

What is the major tissue, that stores triacylglycerol produced by the liver in the fed state? How is it transported from the liver to this tissue?

Entering the Krebs cycle, only occurs if carbon skeletons are needed for biosynthesis.

What is the minor fate of acetyl CoA produced by the liver in the fed state?

glucose

What is the only circulating fuel used by the brain in the fed and early-fasting state?

Lactate: exported to the blood blood and taken up by the kidneys and liver. They use lactate as a substrate for energy metabolism and gluconeogenesis.

What is the product of RBC energy metabolism?

Glucose 6-phosphate can actually enter two pathways and occurs once glycogen stores are replenished. (1) Pentose phosphate pathway (purple): glucose 6-phosphate ⟶ ribose 5-phosphate ⟶ nucleotides (used to synthesize DNA, RNA, NAD, ATP) (2) Glycolysis (yellow): glucose 6-phosphate ⟶ pyruvate ⟶ acetyl CoA

What is the second metabolic pathway glucose 6-phosphate undergoes in the liver during the fed state? When does it occur?

(1) Increased glucose transport: The transient increase in plasma glucose and insulin after a carbohydrate-rich meal leads to an increase in glucose transport into muscle cells (myocytes) by GLUT-4, thereby reducing blood glucose. Glucose is phosphorylated to glucose 6-phosphate by hexokinase and metabolized to meet the energy needs of myocytes. The utilization of glucose only occurs after a meal when insulin is high, allowing for glucose to be shunted to the brain when fasting.

What occurs in muscle after consuming a carbohydrate rich meal?

Increased glycogenesis: Insulin dependent GLUT4 transporters, insert into the plasma membrane, to increase the uptake of plasma glucose. Glucose is phosphorylated to glucose 6-phosphate by hexokinase. Since the muscle isn't contracting it favors glycogen synthesis by glycogen synthase.

What occurs in resting skeletal muscle after consuming a carbohydrate rich meal?

Muscle

What organ requires ATP for mechanical work?

Adipose tissue

What organ stores and releases fatty acids?

Liver

What organ tissue distributes nutrients to maintain metabolite levels allowing us to survive in the absence of food.

Brain

What organ tissue requires specialized signal transduction to process information and generate signals (hormones, growth factors, etc.)?

Distribution and concentration of macromolecules from a meal. Predominantly determined by the carbohydrate content, but proteins and lipids also stimulate insulin secretion. Also, the complexity of the carbohydrates determine the rate at which insulin is released. So, simple sugars will illustrate faster and larger spikes.

What other factors regulate the insulin/glucagon ratio?

acetoacetate

What structure is illustrated?

acetoactate

What structure is illustrated?

β-hydroxybutyrate

What structure is illustrated?

Top structure = pyruvic acid (used by the liver) Bottom structure = Acetoacetic acid

What structures are illustrated? Which of these is used by the liver as a fuel source?

GLUT3 (Km for glucose = 1.3)

What transporter allows the brain to uptake glucose?

The conversion of fatty acids into lipids for hepatocytes during the fed state. They are used to build cell membranes for proliferation.

Whats illustrated at point 1 (fed state in liver)?

Excess fatty acids can be used to synthesize cholesterol, and then bile salts/bile acids.

Whats illustrated at point 6 (fed state in liver)?

Usually from slow, but active muscle contractions, like walking. If you run you mostly utilize glycogen, since there isn't enough oxygen. However, when you walk fatty acids are used, because oxygen is present to fully oxidize them.

When does fat burning occur?

Fatty acids only undergo beta-oxidation, during the fed state, when alpha-ketoacids are not available like after consumption of a low protein meal.

When does point 2 occur (fed state in liver)?

Produced from fatty acids in the liver In prolonged starvation/late fasting, the liver is flooded with fatty acids mobilized from adipose tissue. Resulting in an increase in hepatic acetyl CoA from the β-oxidation of fatty acids. Recall, acetyl CoA inhibits pyruvate dehydrogenase and activates pyruvate carboxylase (PC). Pyruvate carboxylase catalyzes the production of oxaloacetate (OAA), which is used for gluconeogenesis in the liver rather than for the TCA cycle. At the same, time β-oxidation decreases the NAD+/NADH ratio, and the subsequent increase in NADH shifts OAA's conversion to malate. Since OAA isn't available to react with acetyl CoA, it's used for ketogenesis.

Where are beta-keto acids produced (ketogenesis)?

Cytosol

Where are the enzymes for glycolysis, the pentose phosphate pathway, and fatty acid synthesis localized?

Mitochodonria

Where are the enzymes for the citric acid cycle, β-oxidation of fatty acids, ketogenesis, and respiration localized?

(+) Glucokinase (increased expression): controls the rate of glucose phosphorylation in the liver (+) GLUT4: Glucose uptake in muscle and adipocytes (+) Pyruvate Dehydrogenase Complex: promotes acetyl CoA generation in liver and muscle (+) Glycogen synthase: regulates glycogen synthesis in liver and muscle (+) Glycogen phosphorylase: glycogen breakdown in liver and muscle is decreased (+) Phosphofructokinase 1: regulates glycolysis and controls pyruvate generation in liver and muscle (stimulated by insulin's effect on phosphofructokinase 2) (+) Acetyl CoA carboxylase: fatty acid synthesis in the liver (+) Lipoprotein lipase: triacylglycerol synthesis in adipose tissue

Which enzymes that regulate glucose homeostasis, by promoting the uptake of glucose, are stimulated by insulin?

Preadipocytes have vacuoles that are capable of receiving and storing triacylglycerol. They have many vacuoles that fill with lipids during maturation. Eventually these vacuoles fuse together forming one large vacuole, that stores a lot of lipids and pushes all organelles outward.

Why are adipocytes great at storing energy sources, almost like a biological pantry?

Because their main function is the storage of fuel in the form of triacylglycerol. Fat stored in the adipose tissue is derived from dietary fatty acids (delivered by chylomicrons = major form) and from the endogenous synthesis of fatty acids; mostly in the liver (delivered by VLDL = minor form)

Why are all organelles are pushed to the exterior in mature adipocytes?

The blood brain barrier prevents the uptake of fatty acids.

Why does the brain use ketone bodies, rather than fatty acids (which are the precursor for ketone bodies) for fuel?

Catalyzes the formation of fatty acyl CoA quickly because fatty acids should not be freely present inside cells.

Why is fatty acyl synthase important to maintaining a healthy cellular environment?

It lacks fuel stores such as glycogen and triacylglycerol; so it requires a continuous supply of glucose. Once, plasma glucose falls below 2.2 mM, glycolysis will slow down and ketone bodies will be used to minimize protein degradation.

Why is maintaining blood glucose critical for survival of the brain?

Availability of the substrates acetyl CoA (from glycolysis) and NADPH (from pentose phosphate pathway). Insulins activation of acetyl-CoA carboxylase (ACC), which is dephosphorylated through inactivation of AMPK. Recall, inactivity of AMPK favors dephosphorylation. ACC is also stimulated by the presence of its allosteric activator, citrate.

Why is the generation of fatty acids in the liver favorable in the fed state?

Point 7, because the lipoproteins (VLDL) have triacylglycerol incorporated into their structures. Not many free fatty acids will be released because the body wants as many energy stores as possible.

Will point 7 or 8 predominate, during the fed state in the liver?