Metabolism Exam 3 Study Guide

Iron-Lipids

What are the food source, structure, and bioavailability differences between heme and non-heme iron?

• Heme Iron- iron associated with the protoporphyrin ring in Heme → found in meat products (liver oysters, beef, etc).

  • HIGHLY Bioavailable!

• Non-Heme Iron- iron in organic chelates (like ferric citrate or ferrous fumarate) or constituents of bio-molecules (like ferritin) → found mainly in plant products (oatmeal, beans, lentils, tofu, spinach) with some in meat as well (in the form of biomolecules).

  • POORLY Bioavailable!

Iron Absorption

1. Free iron enters the duodenum.

2. Fe3+ is reduced to Fe2+ by DcytB.

3. Fe2+ is absorbed into the enterocyte by DMT1.

4. Iron leaves the enterocyte by Ferroportin and enters portal blood circulation.

5. Fe2+ is oxidized to Fe3+ by Hephaestin so it can bind to transferrin for transport.

What does Hepcidin do at the molecular level?

Hepcidin regulates whole body iron metabolism.

How does hepcidin control the amount of iron in the plasma?

• Hepcidin is the brakes of iron absorption → binds to Ferroportin (protein that transports iron OUT of the enterocyte), initiating its degradation.

  • Iron is trapped in the enterocyte and will not enter circulation!

• Hepcidin also inhibits the release of iron from the Reticuloendothelial System (RES), further keeping iron out of circulation.

How is cellular iron status maintained by post-transcriptional regulation of ferritin and transferrin receptors?

Iron Response Element (IRE) = region of mRNA that codes for proteins involved in iron.

Iron Regulatory Protein (IRP) = protein that interacts with IRE to influence translation of proteins involved in iron.

• Low Iron:

  • IRP binds to the IRE, making the region of mRNA that codes for ferritin inaccessible → No Ferritin Made!

  • IRP binds to IRE, stabilizing the region of mRNA that codes for transferrin → Transferrin is Made!

  • Iron does NOT want to be stored when iron is low, it wants to be transported and available for use!

• High Iron:

  • Iron binds to IRP, releasing it from the IRE and unblocking the mRNA region → Ferritin is Made!

  • Iron binds to IRP, releasing it from the IRE, making the mRNA unstable and degraded → No Transferrin is Made!

  • Iron cannot be actively excreted so it wants to be stored in high concentrations!

What does a serum ferritin test measure and how is this test different from hemoglobin level?

Measures the amount of ferritin (storage protein) in the blood, which reflects the body’s total iron stores.

Low Hb levels indicate anemia, however it is NOT specific for iron → just because you have low Hb does not necessarily mean you have Iron-deficiency anemia.

What is a potential limitation of the serum ferritin test?

It is NOT routinely measured—you must ask/demand!

What does low serum ferritin indicate?

Iron deficiency (<30 ng/L)

How to calculate iron stores from serum ferritin?

1 ng/mL of serum ferritin = ~8mg of stored iron

Multiply serum ferritin by 8 to get mg of stored iron!

Causes of Iron Deficiency

• Blood loss

  • Menstruation

  • GI Bleeding

  • Genitourinary Tract

  • Respiratory Tract

  • Blood Donation

• Growth/Pregnancy

• Diet Low in Bioavailable Iron

• Impaired Absorption

  • Gastric Surgery

  • Hypochlorhydria

Prevalence of Iron Deficiency— what groups are most at risk?

Infants, Children, Women of Reproductive Age

What are consequences of iron deficiency WITHOUT anemia?

• Poor cognitive performance

• Decreased immune function

• Reduced exercise + endurance capacity

• Anemia

• Growth retardation

• Poor pregnancy outcomes

Which form of supplemental iron is most commonly recommended by doctors to correct iron deficiency and iron deficiency anemia? What is a common side effect of this form?

Ferrous Sulfate → common side effects: nausea, flatulence, abdominal pain, diarrhea, constipation, melena.

What form of supplemental iron is associated with the least number of side effects?

Iron Bisglycinate

What are the causes and prevalence of iron overload? What groups are most at risk?

• Number 1 cause is Hereditary Hemochromatosis!

  • 1 in 8 are heterozygous

  • 1 in 200 are homozygous

• Affects individuals are Northern European descent (especially Irish/Celtic).

Hereditary Hemachromatosis

A genetic disease resulting in the accumulation of excess iron in the body.

• Caused by a single point mutation in the HFE gene that causes low Hepcidin (regulates total body iron metabolism).

How the regulation of whole-body iron metabolism different from other all other minerals?

• Iron is never actively excreted, even if large amounts are consumed.

  • In conditions of excess iron, it is stored.

• All other minerals have an active excretion pathway.

Copper Absorption

1. Free Copper enters the duodenum.

2. Cu2+ is reduced to Cu+ by a reductase.

3. Cu+ is transported into the enterocyte via CRT-1.

4. ATP7A pumps copper either into TGN for cuproenzyme synthesis or, in times of excess, to the basolateral membrane for transport into the portal blood by a different ATP7A.

5. Cu+ is oxidized to Cu2+ for transport via albumin/macroglobulin.

Copper Chaperones

Bind intracellular copper so it cannot catalyze ROS formation.

1. CCS → delivers copper to SOD1.

2. ATOX1 → delivers copper to TGN.

3. COX17 → delivers copper into mitochondria.

What is the function of ceruloplasmin?

How is ceruloplasmin similar and different from hephaestin?

Main Differences Between Whole-Body Iron and Copper Metabolism

What are the two main disorders of copper metabolism in humans?

Menke’s Disease and Wilson’s Disease

Causes and Clinical Symptoms of Menke’s Disease

• Causes: defect in ATP7A function → copper cannot exit the enterocyte, leading to low copper in plasma, liver, and brain.

• “Kinky Hair Disease”

• Clinical Symptoms: stubby, white hair, slow growth, neural degeneration, seizures, depigmentation of hair and skin, Death at a young age.

Causes and Clinical Symptoms of Wilson’s Disease

• Causes: defect in ATB7B function → copper cannot exit liver and efflux into bile, leading to accumulation (also in brain).

• Clinical Symptoms: Kayser-Fleisher rings

• Treatment: Penicillamine and high-dose Zinc.

Food Forms of Selenium

• Organic: Selenium as a part of the amino acids methionine and cysteine.

  • Selenomethionine- main form in plants

  • Selenocysteine- main form in animals

  • Very bioavailable → 100% absorbed!

• Inorganic: selenium chelates (Selenate and Selenite).

  • Plants, supplements, animal feed.

How is organic selenium absorbed?

How does selenium absorption change in deficiency? How does this compare to Fe, Cu, Zn?

Selenium absorption does NOT increase in deficiency. Fe, Cu, and Zn absorption are all upregulated during deficiency by increasing the number of transporters.

How is excess selenium excreted?

• In the urine as Methylselenol (CH3SeH) and via the breath as Dimethylselenide.

• Only pharmacologic doses are expired in the breath.

What is Selenocysteine and how is it different from cysteine?

• Selenocysteine is a cysteine residue that contains Se where is usually contains S.

• Selenocysteine fulfills chemical functions that conventional cysteine residues cannot.

• It occurs in 25 proteins in the human proteome.

Why is selenium sometimes considered an antioxidant?

Selenium is a component in Selenoproteins, some of which have the antioxidant function of scavenging free radicals. For example…

• Selenoprotein P (SELP)- reduces the Peroxynitrite radical.

• Glutathione Peroxidase- reduces hydrogen peroxide species.

What is Glutathione Peroxidase?

• An antioxidant enzyme that contains selenium, making it a Selenoprotein.

  • Reduces hydrogen peroxide species produced as by-products of biochemical reaction.

• It was the first selenoprotein ever identified.

• Accounts for >50% of total body Se.

How is Glutathione Peroxidase similar and different from Superoxide Dismutase (SOD)?

• Superoxide Dismutase also reduces peroxide radicals.

• GPD requires Se, while SOD requires Cu and Fe.

Causes and Effects of Dietary Selenium Toxicity

Causes: Chronic consumption of plants grown in high-Se soil.

Effects:

• Changes in nail structure

• Loss of hair and nails

• Lesions of the skin and nervous system

• Nausea

• Diarrhea

• Weakness

Which Se-containing proteins function in iodine homeostatsis?

Iodothyronine deiodinases

What effect does selenium soil concentration have on selenium nutritional status in humans?

• Selenium concentrations can greatly affect selenium nutritional status.

• Selenium deficiency was first identified in areas with low Se conc in the soil.

• Selenium toxicity was was first identified in areas with high Se conc in the soil.

What is the primary function of iodine in the body?

Iodine Storage

What are the differences between T4, T3, and rT3?

How is thyroid hormone transported in the plasma → How does this related to Vitamin A transport?

How is the function of T3 similar to 1,25-dihydroxy D3?

Prevalence, Effects, and Treatment of Iodine Deficiency

What are the potential adverse effects of iodine deficiency in pregnancy?

Intracellular vs Extracellular Conc of Sodium, Potassium, and Chloride

• Sodium = Major Extracellular Cation

• Potassium = Major Intracellular Cation

• Chloride = Major Extracellular Anion

Intracellular Na/K ratio: 1:10

Extracellular Na/K ratio: 28:1

Sodium Functions

• Membrane transport

• Nerve and Muscle Cells (Action Potentials)

• Water balance

  • Osmotic Pressure

  • Intracellular K+ (Na/K Pump)

  • Circulatory volume (blood pressure)

Potassium Functions

• Blood K

• Blood pH and acid/base balance

• Protein and glycogen synthesis

• Membrane/Action Potentials (Nerve, Muscle Cells)

Sodium Absorption

Taken up into enterocytes on apical membrane via SGLT1 and pumped into portal blood via Na/K-ATPase (active transport) on basolateral membrane.

Also passive diffusion in jejunum and colon.

What are the types of dietary CHOs? Examples? Typical food sources of each?

What are the functions of dietary fibers in human health?

• Slows stomach emptying (soluble fibers)

• “Binding” action for cholesterol (prevents bile recycling)

• Exercise for gut muscles.

• Softer stool

• Decreases transit time in the gut

• Releases a small amount of energy (~1.5 kcal) as gut microbes break down

CHO Digestion and Absorption

How does Gatorade and Pedialyte work to enhance hydration at the molecular level?

• Gatorade and Pedialyte capitalize on the function of SGLT 1 for oral rehydration.

• SGLT 1 is a symporter for glucose, sodium, and water.

  • For every 1 molecule of glucose, 1 molecule of sodium is transported.

  • For every 1 glucose and sodium, 245 molecules of water are being transported.

How and where are B-Vitamins involved in CHO metabolism?

• Thiamin (B1), Riboflavin (B2), Niacin (B3), and Pyroxidine (B6) are all important for CHO Metabolism

• B1- Glycolysis and the Citrate Cycle

  • Coenzyme for Transketolase (Glycolysis) and Pyruvate Dehydrogenase (Citrate)

• B6- Glycogenolysis and Citrate Cycle

  • Coenzyme for Glycogen Phosphorylase (bound to PLP) and Aminotransferase (Citrate)

Advantages and Disadvantages of Sugar Alcohols

Advantages and Disadvantages of Erythritol → Why is Erythritol special?

Protein Digestion and Absorption

Essential Amino Acids

Which vitamins are needed for protein metabolism? What general metabolic pathway do they participate in?

What are the protein requirements for resistance training?

What are the protein requirements for endurance exercise?

How can different dietary proteins effect muscle-protein synethsis?

Why is whey protein superior for building muscle?

Whey protein contains higher amounts of Lysine, the amino acid responsible for signaling the start of muscle-protein synthesis

Where are lipids found in food?

Lipid Digestion

Types of Fatty Acids and Structural Differences

Which fatty acids are essential and why?

What are good dietary sources of omega 6 FAs?

What are good dietary sources of omega 3 FAs?

What are good dietary sources of monounsaturated FAs?

How is coconut oil different from most other oils?

What are the differences between medium-chain triglycerides (MCTs) and short-chain fatty acids (SCFAs)?

How are MCTs absorbed and metabolized?

How are SCFAs absorbed and metabolized?

What is the importance of DHA?

What are potential benefits of DHA and EPA?

What is the relationship between omega-3 fatty acids and cardiovascular disease?

What are he effects of omega-3-fatty acids on plasma triglycerides and cholesterol?

What is the VITAL Trial?

What were the main conclusions of the VITAL trial regarding omega-3 fatty acids on cardiovascular disease and cancer?