Course Syllabus

NUTR 443 - Nutrition II

Course Description: (5 credits) Prerequisites, NUTR 341, Chem 113 or Chem Chem 372, Zool 270 or 342 or permission.  Effect of nutritional and physiological state on the regulation of carbohydrate, lipid, and protein metabolism.  Metabolic and physiological role of vitamins and mineral.

Winter             2007
Instructor:      David L. Gee, Ph.D.
Office:             PE 109
Phone:             963-2772
Office Hours:  by appointment
                       drop in: TuTh 2-3PM
                        or by email (geed@cwu.edu)

Text:      Metabolism at a Glance, 2nd ed., JG Salway, 1999
               Krause's Food, Nutritio, & Diet Therapy, 11th ed., K Mahan & S Escott-Stump, 2004
     

Additional useful (optional) reading: The Medical Biochemistry Page.  Michael  W. King, PhD, Indiana University School of Medicine
 
 

Student Outcomes:

1. The student will have a basic understanding of the function and regulation of metabolic pathways as they relate to nutrition.

2. The student will understand how control of metabolic pathways in different organs are integrated in the intact animal.

3. The student will recognize the role of vitamins and minerals in metabolism and regulation.

4. The student will know the scientific principles of human nutrition in health and disease.
 
 
 
 
 
 

Letter Grade:

  >90% A's
  >80% B's
  >65% C's
 
 

TENTATIVE COURSE OUTLINE:
 
 

Week	Topic	Required Readings
1	Enzyme Regulation - an Overview  Regulation of Carbohydrate Metabolism	MAAG 1 (Regulation of Enzyme Activity & Allosteric Enzymes)
2	Hormonal Regulation Hexokinase/Glucokinase Phosphofructokinase	MAAG 5, 20 (Regulation of Blood Glucose Levels) (The Hexokinase Reaction, Regulation of Glycolysis)
3	Cori cycle Glycogen metabolism	MAAG 7, 8, 16, 17, 18, 19 (Glycogen Metabolism)
4	Pyruvate metabolism Gluconeogenesis	MAAG 23, 24 (Metabolic Fates of Pyruvate) (Gluconeogenesis) CHO metabolism during exercise - Anna Zorn
5	Regulation of Lipid Metabolism Fatty acid synthesis	MAAG 10, 11, 13
6	Lipoprotein metabolism  Adipose tissue  Ketosis  (Cholesterol Homeostasis)	MAAG 14, 15, 25, 26, 27, 28
7	Protein Catabolism	MAAG 33, 36, 38, 39
8	Water Soluble Vitamins	FNDT Chapter 4
9	Oxidant Tissue Injury and Nutritional Antioxidants Fat Soluble Vitamins	FNDT Chapter 4
10	Minerals	FNDT Chapter 5

 
 
 

Enzyme Regulation
David Gee, PhD
NUTR 443 -Nutrition II

Importance of Regulating Metabolic Pathways
Changing Environment
Starvation vs. Feeding
Low Protein vs. High Protein
Rest vs Exercising

Importance of Regulating Metabolic Pathways
Adaptation of metabolism to meet needs.
Organ function and body priorities affect regulation differently in different tissues.

Characteristics of Regulatory Enzymes
Catalyze a step EARLY in a metabolic pathway.
Catalyze early step UNIQUE in a metabolic pathway.

Characteristics of Regulatory Enzymes
Catalyze an IRREVERSIBLE STEP in a metabolic pathway.
Catalyze a SLOW/RATE LIMITING STEP in a metabolic pathway.

Mechanisms of Enzyme Regulation
Regulation of Enzyme Quantity
Activation and Inactivation of Enzymes
Regulation of Catalytic Efficiency

Regulation of Enzyme Quantity
Enzyme quantity is in steady state
Quantity is determined by:
Input (rate of synthesis)
Output (rate of degradation)

Regulating Rate of Enzyme Synthesis
Induction of enzyme synthesis
presence of an inducer increases the rate of synthesis
example:
E. coli and B-glucosidase (lactase)

Regulating Rate of Enzyme Synthesis
Repression of enzyme synthesis
presence of a repressor decreases rate of synthesis
example:
E. coli and B-glucosidase

Regulation of Enzyme Quantity
regulation of enzyme quantity primarily at rate of synthesis
Inducible Enzymes
amount of enzyme varies with physiological condition
Constititive Enzymes
amount of enzyme relatively constant

Regulation of Fatty Acid Synthase Gene
FAS a regulatory enzyme in fat synthesis from excessive CHO or PRO intake.
Liver and adipose enzyme
FAS is an inducible enzyme
FAS activity in chick hepatocytes

Regulation of Fatty Acid Synthase Gene
FAS is induced in the fed state in the presence of insulin + T3.
This allows fats to be synthesized from the excess CHO/PRO during feeding.
FAS is repressed in the starved state in the presence of glucagon.
This prevents fats from being made from glucose and amino acids.

Mechanisms of Enzyme Regulation
Regulation of Enzyme Quantity
Activation and Inactivation of Enzymes
Regulation of Catalytic Efficiency

Activation and Inactivation of Regulatory Enzymes
Covalent modification of enzymes
Zymogen Activation
hydrolysis of peptide bonds
irreversible activation of enzymes

Zymogen Activation
Digestive Enzymes
pepsinogen -> pepsin
chymotrypsinogen -> chymotrypsin
trypsinogen -> trypsin
procarboxypeptidases -> carboxypeptidases

Zymogen Activation
Hormones
Proinsulin -> insulin
Blood clotting
Prothrombin -> thrombin
Fibrinogen -> fibrin

Activation and Inactivation of Regulatory Enzymes
Zymogen Activation
Covalent Modification by phosphorylation and dephosphorylation

Phosphorylation and Dephosphorylation of Enzymes
to key serine and threonine residues
reversible reaction
protein kinases -> phosphorylate
protein phosphatases -> dephosphorylate

Phosphorylation and Dephosphorylation of Enzymes
Pyruvate Dehydrogenase
links glycolysis with Krebs’ Cycle
inactive when phosphorylated
Glycogen Synthetase
inactive when phosphorylated

Phosphorylation and Dephosphorylation of Enzymes
Phosphorylase
regulatory enzyme of glycogen degradation
active when phosphorylated

Regulation of Phosphorylase
Degradation of glycogen is needed for:
low blood sugar (hypoglycemia)
strenuous exercise (fight or flight)

Regulation of Phosphorylase
Key hormones:
epinephrine (stress, abrupt hypoglycemia)
glucagon (fasting)

Mechanisms of Enzyme Regulation
Regulation of Enzyme Quantity
Activation and Inactivation of Enzymes
Regulation of Catalytic Efficiency

Regulation of Catalytic Efficiency
Michaelis Menten Kinetics
hyperbolic kinetics
Vmax
Km
non-regulatory enzymes

Regulation of Catalytic Efficiency
Allosteric Enzymes
multiple binding sites
catalytic site(s)
allosteric (regulatory) site(s)
binding at one site affects binding and activity at other sites

Regulation of Catalytic Efficiency
Allosteric activators
increase Vmax
decrease Km
Allosteric inhibitors
decrease Vmax
increase the Km

Regulation of Carbohydrate Metabolism
David L. Gee, PhD
NUTR 443 - Nutrition II
Hormonal Effects
Insulin
Glucagon
Epinephrine

Insulin
Insulin Effects
Increase in cell permeability
glucose
other monosaccharides (except fructose)
amino acids
other (Ca, K, PO4, nucleotides)

Insulin Effects
Increases rate of protein synthesis
Induces enzymes of glycolysis
Represses enzymes of gluconeogenesis
Induces protein phosphatases (proteins dephosphorylated)

Insulin Metabolism
Synthesized in pancreas as proinsulin
Activation and release in response to feeding (hyperglycemia)
Degraded in liver
half life = 20 minutes
elevated only during hyperglycemia

Glucagon
synthesized in pancreas
released when blood glucose concentration falls

Glucagon Effects
activates adenyl cyclase
stimulates glycogenolysis
activates hepatic lipase
induces gluconeogenic enzymes
effects antagonistic to insulin

Glucocorticoids (cortisol)
synthesized in adrenal cortex
similar effects as glucagon
effects strongest in extra-hepatic tissues

Cortisol Effects
Induces gluconeogenic enzymes
Increases rate of protein degradation in extra-hepatic tissues (muscle)
Induces enzymes of amino acid degradation

Regulation of Glucose Utilization
Glucose utilized for:
Glycolysis
Glycogen synthesis
Hexose Monophosphate Pathway
If all needs for glucose met, regulate first step.

Hexokinase
glucose + ATP --> G6P + ADP
found in most tissues
constitutive enzyme
low Km
Km = 0.01 - 0.05 mM
[glu] fasting = 5 mM

Regulation of hexokinase
feedback inhibition by G6P
increased G6P reflects glucose needs being met
G6P reduces Vmax by 95%

Glucokinase
HK activity low in liver
GK only found in liver
glucose + ATP --> G6P + ADP

Regulation of glucokinase
Inducible enzyme
induced by insulin
repressed by glucagon
Not inhibited by G6P

Regulation of glucokinase
High Km
Km = 10 mM
[glu] feeding = 8 - 12 mM
GK activity only high during active feeding.

Glucose-6-Phosphatase
liver and kidney cortex
G6P --> glucose + Pi
induced by glucagon
repressed by insulin

Coordinated regulation of GK and G6P’tase
Feeding
insulin induces GK, represses G6Ptase
[glu] is high
convert glucose to G6P

Coordinated regulation of GK and G6P’tase
Post-absorptive state
GK levels high, G6Ptase levels low
[glu] are low
glucose not utilized by liver

Coordinated regulation of GK and G6P’tase
Fasted state
glucagon induces G6Ptase, represses GK
[glu] is low
G6P --> glucose
G6P from glycogenolysis or gluconeogenesis

Regulation of Glycogen Metabolism
Glycogen metabolism
Phosphorylase
regulatory enzyme of glycogen degradation
Glycogen Synthetase
regulatory enzyme of glycogen synthesis

Regulation of Phosphorylase
Activation
Cascade amplification
epinephrine, glucagon
adenylcyclase, cAMP
protein kinase
phosphorylase kinase

Regulation of Phosphorylase
Inactivation
Insulin induces protein p’tases
Phosphorylase p’tase
Phosphorylase inactivated

Regulation of Glycogen Synthetase (GS)
Activation
Insulin induces protein p’tases
GS p’tase
activation of GS

Regulation of GS
Inactivation
glucagon/epinephrine
adenyl cyclase, cAMP
protein kinase
inactivates GS

Integration of glycogen metabolism
Feeding
Insulin induces protein p’tases
proteins dephosphorylated
GS active
Phosphorylase inactive
Liver/muscle making glycogen

Integration of glycogen metabolism
Fasting and exercise
glucagon/epinephrine activate AC
cAMP activate protein kinase
GS inactivated
Phosphorylase activated
Glycogen degraded, glucose produced

Glycogen metabolism - Tissue specific regulation
Muscle
Phosphorylase kinase activated by elevated calcium
Calcium released into sarcoplasm during muscle contraction

Glycogen metabolism - Tissue specific regulation
Liver
Glycogen Synthetase activated by G6P
G6P only elevated during feeding
hi glucose
GK induced

The Cori Cycle
Muscle glycogen for blood glucose?
Cori Cycle
Net energy cost is 3 ATP/glucose from muscle glycogen
0 ATP/glucose from liver glycogen

Regulation of Glycolysis
Function in extrahepatic tissues
energy production
Function in liver (adipose)
production of pyruvate & acetyl CoA for fatty acid synthesis

Regulation of PFK in Muscle
Allosteric inhibition
ATP
indicates high energy state (rest)
citrate
indicates FA or KB available
indicates Krebs’ cycle full

Regulation of PFK in Muscle
ATP/Citrate effect
when at rest or alternate sources of energy available , then slow glycolysis
Allosteric activators
ADP & AMP
indicate low energy
during exercise (heavy), increase glycolysis

Regulation of PFK in Muscle
Allosteric inhibition by
ATP & Citrate
Allosteric activation by
ADP & AMP
PFK in liver is inducible
induced by insulin
repressed by glucagon

Regulation of PFK in Liver
Activated by F6P
F6P elevated only during active feeding
hi GK
hi glucose
Action of F6P overrides ATP & citrate inhibitory effects
(action of F6P on PFK is indirect and complicated)

Regulation of FDPtase
Liver & Kidney
Induced by glucagon
Repressed by insulin
F6P allosteric inhibitor
Prevents PFK/FDPtase futile cycle

Regulation of Pyruvate Metabolism
Metabolic fates of pyruvic acid
Red blood cells
to lactic acid (to Cori Cycle)

Metabolic Fates of Pyruvate
Muscle
to lactic acid via lactate dehydrogenase (LDH)
during “anerobic” exercise
to acetyl CoA via pyruvate dehydrogenase (PDH)
for energy in TCA cycle

Metabolic Fates of Pyruvate
Liver
to lactate (or back)
to acetyl CoA for
fatty acid synthesis
energy via TCA cycle
to oxaloacetic acid (OAA)
for gluconeogenesis

Importance of regulating the fate of  pyruvate.
pyruvate is glucogenic
acetyl CoA is ketogenic
in starvation, it is important to preserve the glucogenic potential of pyruvate when possible

Regulation of PDH
Regulation by Active/Inactive Forms
active form is dephosphorylated
Regulation of Catalytic Efficiency

Regulation of PDH
Regulation of catalytic efficiency
allosteric inhibitors
acetyl CoA
NADH
feedback inhibition 

Regulation of PDH
Covalent Modification of PDH
PDH active in dephosphorylated form
PDH inactive in phosphorylated form

Inactivation of PDH
PDH Kinase inactivates PDH
PDH Kinase inhibited by
ADP
low energy, inhibit PDH Kinase, keep PDH active
Pyruvate
CHO feeding, keep PDH active

PDH Kinase activated by
ATP
High energy (resting), activate PDH kinase, inactivate PDH

Activation of PDH
PDH phosphatase activates PDH
PDH p’tase induced by insulin
feeding results in active PDH for fat synthesis
PDH p’tase activated by Calcium
Muscle contraction, hi Ca, activate PDH p’tase, activate PDH
ATP & Citrate inhibit PDH p’tase
high energy, TCA full, inhibit activation of PDH
 
 

Regulation of PC
Allosteric regulation of PC
Acetyl CoA activates
liver has alternate fuel (FA oxidation)
ATP activates
liver has adequate energy
ADP inhibits
liver has inadequate energy

Regulation of PEPCK
Inducible enzyme
Glucagon induces
Insulin represses
Malate shuttle
No OAA mitochondrial transport protein
Malate dehydrogenase equilibrium reaction towards OAA with high NADH from fat oxidation

Coordinated regulation of PC and PDH in liver
Fed State
make fat, don’t make glucose
Insulin
represses PC, PEPCK, FDPtase, G6Ptase
activates PDH
Induces PDH p’tase

Coordinated regulation of PC and PDH in liver
Starvation
Make glucose, don’t oxidize pyruvate
high Acetyl CoA
plenty of energy from B-oxidation of fats
Hi NADH inhibits ICDH, slows TCA cycle
inhibits PDH
activates PC
Also glucagon activates protein kinase
Inactivates pyruvate kinase
Prevents futile cycle
 
 
 
 
 
 
 

Regulation of Lipid Metabolism
David L. Gee, PhD
NUTR 443 - Nutrition II

Regulation of Fatty Acid Synthesis
Conversion of acetyl-CoA to fatty acids
Sources of Acetyl-CoA
excess carbohydrates (glucose)
excess protein (amino acids)
Liver and adipose tissue
Cytosolic pathway
B-oxidation mitochondrial pathway

Fatty Acid Synthesis Pathway
Acetyl CoA Carboxylase
acetyl-CoA + CO2 + ATP ---->
malonyl-CoA + ADP + Pi
reaction
requires biotin

Fatty Acid Synthesis Pathway
Fatty Acid Synthetase
reaction
general mechanism
1. elongate by 2C from malonylCoA
2. reduce elongated FA with 2 NADPH

Cellular Site of FA Synthesis
FAS & acetylCoA carboxylase are cytoplasmic enzymes
acetylCoA formed in mitochondria from PDH
acetylCoA too large and charged to be transported through mitochodrial membrane

Pyruvate - Malate Cycle
pathway
purpose:
transport AcetylCoA from mitochondria to cytoplasm
synthesis of 50% of NADPH needed for FA synthesis

Regulation of FA Synthesis
Regulation of enzyme amount
Induced in fed, hi CHO state by insulin
Repressed in starved state by glucagon

Inducible Enzymes of FA Synthesis
Acetyl CoA carboxylase
Fatty acid synthetase
Malic enzyme
G6P dehydrogenase
Citrate lyase

Regulation of Acetyl CoA Carboxylase
covalent modification
active in dephosphorylated form
insulin induces ACC p’tase
glucagon activates (via cAMP) ACC kinase --> inactivates ACC

Regulation of Acetyl CoA Carboxylase
Allosteric regulation of ACC
activated by citrate
feed ahead activation
hi CHO diet, hi PDH activity, hi AcCoA, hi citrate
low TCA due to hi energy (hi NADH inhibits isocitrate dehydrogenase, reg NZ TCA cycle)

Functions of Citrate in FA Synthesis
carries AcCoA from mito to cyto
signals activation of ACC for FA synthesis
carries carbons from mito to cyto for oxidation and production of NADPH

Regulation of Acetyl CoA Carboxylase
Allosteric inhibition by FA-CoA
signal that esterification of FA to TG is limiting, slow down FA synthesis
may signal cell in fasted state, FA-CoA from hi FFA during starvation

Transport of Lipids - Lipoprotein Metabolism
Lipoprotein structure
Classes of lipoproteins
Chylomicrons
Very Low Density Lipoprotein (VLDL)
Low Density Lipoprotein (LDL)
High Density Lipoprotein (HDL)

Chylomicron Metabolism
transport of dietary fat
nascent chylomicron made in intestinal absorptive cell
complete chylomicron formed in blood with HDL

Chylomicron Metabolism
hydrolysis of TG chylomicron via lipoprotein lipase in peripheral tissues to remnant
remnant removed by liver

VLDL Metabolism
Transport of endogenous TG
Nascent VLDL synthesized  in liver
Complete VLDL formed in blood with HDL

VLDL Metabolism
Hydrolysis if VLDL-TG by lipoprotein lipase in peripheral tissues to form IDL
50% of IDL removed by liver
50% of IDL metabolized to LDL
LDL is primary carrier of cholesterol
LDL removed by LDL-receptors on surface of all cells

Lipoprotein Lipase
Location:
endothelial wall of capillary bed of extrahepatic tissues
Action:
TG ---> 3 FA + glycerol
FA absorbed by tissue
glycerol to liver

Regulation of LPL
Passive Regulation
Heart Km = 0.07 mM
Adipose Km = 0.7 mM
Heart LPL active during feeding or fasting
Adipose LPL active only during feeding

Regulation of LPL
LPL is an inducible enzyme
Insulin (feeding) induces LPL
Glucagon/Cortisol (starvation) represses LPL
Pregnancy increases LPL activity
Lactation increases LPL in mammary tissue.

Regulation of Lipid Metabolism in Adipose Tissue
Insulin effects
Adipose highly sensitive to insulin
Increases glucose uptake
Increases glycolysis & fatty acid synthesis
Insulin stimulates synthesis and storage of lipids in adipocytes

Regulation of Lipid Metabolism in Adipose Tissue
Hormone Sensitive Lipase
TG ---> glycerol + 3 FA
Located inside adipocyte
(LPL located in capillary wall)

Hormone Sensitive Lipase
Regulation - Covalent Modification
Active in phosphorylated form
HSL-kinase activated by glucagon/cortisol via cAMP
Inactive in dephosphorylated form
HSL-p’tase induced by insulin

Integration of Lipid Metabolism in Adipose Tissue - FA/TG cycle
Feeding
Insulin increases
glucose uptake
LPL activity
glycolysis - glycerol-P synthesis
fatty acid synthesis
Insulin inactivates HSL
Feeding results in storing of fats

Integration of Lipid Metabolism in Adipose Tissue - FA/TG cycle
Fasting
Lack of Insulin
decreases glucose uptake
decreases glycolysis & Glycerol-P
decreases FA synthesis
Glucagon/Cortisol
activates HSL
Fasting results in fat mobilization

Regulation of Beta-Oxidation
Rate of B-oxidation proportional to [FFA]
Sources of FFA
lipolysis of stored fat by HSL
hydrolysis of lipoprotein TG by LPL
hydrolysis of hepatic TG by hepatic lipase (via cAMP)
Regulation of Beta-Oxidation

Energy state of the cell
[NAD] limiting
hi energy state - hi [NADH], lo [NAD]
hi [NADH]/[NAD] --> lo B-oxidation
lo energy state --> lo [NADH]/[NAD]
---> hi B oxidation

Regulation of Beta-Oxidation
Carnitine-Acyl Transferase
function: transport of FA into mitochondria

Regulation of CAT
CAT allosterically inhibited by malonyl-CoA
feeding, hi malonyl-CoA (ACC)
avoid futile cycle between FA synthesis in cytoplasm and B-oxidation of FA in mitochondria

Regulation of CAT
Fasting
low [malonyl-CoA]
no inhibition of CAT
allows FA (from FFA) to be transported to mitochondria for B-oxidation

Ketogenesis
Partial oxidation of FA
in liver
forming
acetoacetic acid
B-hydroxy-butyric acid
acetone
(“ketone bodies”)

Conditions Resulting in Ketogenesis
Starvation (mild)
Exercise (endurance, mild)
Hi fat, low CHO diets (mild)
Type 1 diabetes mellitus
severe
ketoacidosis
ketonuria

Purpose of Ketogenesis
During starvation & prolonged exercise, liver has a surplus of FFA
Production of KB by liver allows alternate sources of energy for:
muscle for exercise
brain adapts to using KB instead of glucose during prolonged starvation

Factors Resulting in Ketogenesis
Excess Availability of FFA
liver extracts 30% of plasma FFA
amount is in excess of liver energy needs
liver only partially oxidizes FA to KB

Factors Resulting in Ketogenesis
Limited availability of glycerol phosphate
starvation results in very low hepatic glycolysis
low GP prevents re-esterification of FA to form VLDL-TG

Factors Resulting in Ketogenesis
Limited Availability of OAA
OAA used for gluconeogenesis
high NADH/NAD ratio (hi energy, hi B-oxidation) favors OAA -> Malate
Acetyl-CoA not used efficiently in Krebs’ Cycle

Ketone Body Utilization
KB not used by liver
Enzymes for activation of Acetoacetate to AcAc-CoA only in extra-hepatic tissue
Rate of KB utilization proportional to [KB], up to 70mg/dl  -> ketonuria
Adaptation of brain

Integration of Metabolism
Fasted state
2 days to 2-3 weeks
Starved state
 beyond 2-3 weeks

Catabolic Stress Response State
response to trauma or severe illness

Regulation of Cholesterol Metabolism
Cholesterol carrying lipoproteins
LDL-C
70% of TC
HDL-C
20% of TC
VLDL-C
10% of TC

Regulation of Cholesterol Synthesis
Liver and Small Intestine
approx 500-1000 mg/day
biosynthetic pathway
HMG-CoA Reductase
chief regulatory enzyme

Regulation of HMG CoA Reductase
Inducible Enzyme
hi dietary cholesterol -> lo HMGCR
low dietary choesterol -> hi HMGCR

Regulation of HMG CoA Reductase
Active and Inactive forms
phosphorylated form is inactive
significance?
insulin -> HMGCR P’tase -> active HMGCR
increase cholesterol synthesis ??

Regulation of HMG CoA Reductase
Feedback Regulation
allosteric inhibition?
hi cellular cholesterol
hi bile salt pool
hi chylomicron remnant
hi LDL-C

Regulation of Cellular Cholesterol  Levels
Utilization of cellular cholesterol pool
membrane synthesis
steroid hormone synthesis
bile acid synthesis
storage as cholesterol ester

Regulation of Cellular Cholesterol  Levels
Input into cellular cholesterol pool
Mobilize cholesterol ester storage
Synthesis of cholesterol
Uptake of LDL-C

Regulation of LDL-Receptors
Inducible protein
“up-regulated” when cholesterol pool is low
“down-regulated” when cholesterol pool is high

Effect of Dietary Fatty Acids on LDL-Receptor Activity
hi dietary SFA -> hi LDL-cholesterol
cell membrane FA composition affected by dietary FA composition
membrane hi in SFA are less fluid and decrease LDL-R activity?
membrane hi in UFA are more fluid and increase LDL-R activity?

Effect of Dietary Fatty Acids on LDL-Receptor Activity
hi SFA inhibits ACAT ?
lo ACAT may result in
reduced storage of cholesterol
increased cellular cholesterol pool
down regulation of LDL-R ?

Familial Hypercholesterolemia
Homozygous FH
1/106 births
LDL-R activity very low
LDL-C is 6X higher
MI by age 2, fatal MI 30’s
no other risk factors

Familial Hypercholesterolemia
Heterozygous FH
1/500 births
LDL-C 2X higher
MI by 35 yrs
1/20 of all MI of people under age 60

Other Factors Affecting LDL-R
Subtle genetic factors
Dietary factors
Aging
Obesity

Treatment of Hypercholesterolemia
Dietary modification
Reduction of dietary saturated fat
increases LDL-R activity
Increased monounsaturated fats
increases LDL-R activity

 DietaryTreatment of Hypercholesterolemia
Decrease dietary cholesterol
decreases cellular pool
increases LDL-R activity
Increase dietary fiber (soluble)
increases fecal excretion of bile acids
increases synthesis of bile acids from cholesterol
reduces C pool, increases LDL-R activity

 Pharmacological Treatment of Hypercholesterolemia
Bile Acid Binding Resins
cholestyramine (Questran)
Increases fecal bile acid excretion
Decreases cholesterol pool
Increases LDL-R activity

Pharmacological Treatment of Hypercholesterolemia
Niacin
up to 3 grams per day
nicotinic acid (not niacinamide)
reduces VLDL synthesis
reduces both TG and LDL-C

Pharmacological Treatment of Hypercholesterolemia
Niacin
Skin Flushing
Liver injury
time-release form?
reduces flushing
increases hepatotoxicity?

Extended Release Niacin
Niaspan -
FDA approved, 2yr study 1998
no clinically significant changes in liver function
20% decrease in LDL-C, 27% decrease TG, 28% increase in HDL-C

HMG-CoA Reductase Inhibitors
Statin drugs
Mevacor, Lovastatin
Concerns:
costs
life-long
hepatotoxicity
effective with low fat diet

HMG-CoA Reductase Inhibitors
Cholestin (AJCN Feb 1999)
Red Yeast Rice
Xuezhikang
reduces LDLC by 22%
contains statin class chemicals
dietary supplement?
 

Amino Acid Catabolism
David L. Gee, PhD
Professor of Food Science and Nutrition
Central Washington University

Amino Acid Functions
Protein Synthesis
Synthesis of N-containing compounds
Non-protein functions (catabolic)
energy
gluconeogenesis
lipogenesis

Amino Acid Catabolism
Metabolic fate of carbon skeleton
Metabolic fate of amino acid nitrogen

Metabolic Fate of C-Skeleton
Glucogenic amino acids
ala, arg, asp, cys, glu, gly, his, met, pro, ser, thr, val
Ketogenic amino acids
leu
Both Gluco- & Keto- genic amino acids
ile, lys, phe, trp, tyr

Metabolic fate of AA-N
Urinary nitrogen excretion compounds:
urea
ammonia
uric acid

The Urea Cycle
Metabolic pathway
3ATP + CO2 + NH3 + ASP -> Urea + fumerate + ADP + AMP
analogy to TCA cycle
relationship between TCA and Urea cycle

Functions of Urea Cycle
liver - urea synthesis
high arginase activity
kidney - arginine synthesis
low arginase activity

Regulation of Urea Cycle
Enzymes induced during feeding, repressed during starvation
Carbamyl-P synthetase
allosteric enzymes
active with hi arginine
reflects surplus amino acids

Metabolic fate of AA-Nitrogen
General process of AA-N metabolism
1. Move N into compounds important in transport in blood to liver
2. In liver, move N into compounds important in urea synthesis
3. Synthesize urea in liver, transport to kidneys for excretion in urine

Enzymes Important in AA-N Metabolism
Transaminases
Glutamate Dehydrogenase
Glutamine Synthetase
Glutaminase

Transaminases
Aminotransferases
reaction:
AA-1 + aKA-2 <--> aKA-1 + AA-2
Examples
ALT (alanine transaminase)
SGPT - serum glutamate pyruvate transaminase
AST (aspartate transaminase)
SGOT - serum glutamate oxaloacetate transaminase

Functions of Transamination
Transfers AA-N to compounds important in transport to liver
Transfer AA-N to compounds important in urea synthesis
Synthesis of non-essential amino acids
Removal of aa-N to free C-skeleton for gluconeogenesis, oxidation, lipogenesis

Glutamate Dehydrogenase
GLU + NAD <-> aKG + NADH + NH3
all tissues
Functions
energy production
removing ammonia
freeing C-skeleton of GLU
produces NH3 for urea synthesis

Glutamine Synthetase
GLU + ATP + NH3 -> GLN + ADP + P
All tissues, high in muscle
Removes NH3 from GDH reaction and transports as GLN to liver

Glutaminase
GLN -> GLU + NH3
highest in liver and intestine
frees NH3 in liver for urea synthesis

Amino Acid Metabolism - Fed State
Role of the liver
primary site of urea synthesis
primary site of gluconeogenesis
high activity of AA catabolic enzymes
7/10 EAA catabolized in liver
portal blood

Amino Acid Metabolism - Fed State - Liver
Synthesis of liver proteins - 14%
Synthesis of plasma proteins - 6%
Non-protein uses - 57%
Release of plasma AA - 23%
enriched in BCAA

Amino Acid Metabolism - Fed State - Extra hepatic tissues
Protein synthesis
NEAA synthesis
Energy production
Excess AA and AA-N back to liver
ALA
GLN
other AA

Amino Acid Metabolism - Fasted State - Muscle
Contributes 50% of free AA
> 50% as ALA and GLN
uses some AA for energy

Amino Acid Metabolism - Fasted State - Brain
Takes up BCAA
energy
synthesis of NEAA
Releases AA-N as GLN

Amino Acid Metabolism - Fasted State - Intestine
Takes up ALA and GLN
uses GLN for energy
releases AA-N as
ALA
ammonia

Amino Acid Metabolism - Fasted State - Liver
Takes up all AA except for BCAA
Synthesis of urea from AA-N
Synthesis of glucose from AA-C
 
 

Water Soluble Vitamins
David L. Gee, PhD
NUTR 443 - Nutrition 2
Central Washington University

Thiamin
Structure
pyrimidine ring
thiazole ring
methyl bridge

Chemical Characteristics
Very labile nutrient
Heat
stable in crystalline form
less stable in solution
Alkali - very unstable with heat
baking soda

Chemical Characteristics
Sulfites - decomposes B-1
High cooking/processing losses
heat
leaching

Absorption of B-1
in duodenum
active transport (low thiamin levels)
requires sodium and folic acid
passive transport (hi B-1 levels)

Metabolism of B-1
phosphorylation to active form inside cells (TPP)
transported via portal blood
no significant storage, excess to urine

Biochemical Functions of B-1
Oxidative Decarboxyation Reactions
Pyruvate Dehydrogenase
Pyr+CoA+NAD --> AcCoA+CO2 +NADH
a-keto-glutarate dehydrogenase
aKG+CoA+NAD-->SuccCoA + CO2+NADH
important in CHP/energy metabolism

Biochemical Functions of B-1
Transketolation
HMP pathway
Peripheral Nerve Function
TPP or TPPP
non-cofactor function
mechanism?

Thiamin Deficiency
Beri-Beri
anorexia, fatigue, depression
effects on
cardiovascular system
nervous system

Infantile Beri-Beri
first 6 months
breast milk deficient in B-1
mother w/o symptoms
rapid onset
cyanosis, tachycardia, labored breathing
heart failure and death

Wet Beri Beri
symptoms similar to congestive heart failure
edema - trunk, limbs, face
labored breathing, tachycardia
rapid deterioration
fatal cirulatory collapse
responds rapidly to B-1 supplements

Dry Beri-Beri
no edema
progressive wasting
numbing and weakening of extremities
chronic infections

Assessment of B-1 Status
Urinary thiamin excretion
[pyr + lac] in blood
erythrocyte transketolase activity
stimulation with B-1

Niacin
Structure
Nicotinic Acid = Niacin
Nicotinamide = Niacinamide

Cofactor Forms of B-3
Nicotinamide Adenine Dinucleotide
NAD
nicotinamide-ribose-PP-ribose-adenine
Nicotinamide Adenine Dinucleotide Phosphate
NADP
nicotinamide-ribose-PP-(ribose-P)-adenine

Chemical Characteristics of B-3
relatively stable to
light
heat
oxidation
alkali
major losses due to leaching

Absorption of Dietary B-3
Coenzyme form in food
hydrolysis in small intestine to free vitamin
absorbed in duodenum
nicotinic acid protein bound in corn
requires alkali treatment (lime) to release niacin

Metabolism of B-3
conversion of free vitamin to coenzyme in all cells
no storage
excesses metabolized in liver to variety of chemicals
metabolites excreted in urine

Synthesis of B-3
from Tryptophan
pathway requires B-2 and B-6
60 mg of TRY required to make 1 mg B-3
corn is low in both B-3 and TRY

RDA for B-3
Niacin Equivalents (NE)
1 NE = 1 mg B-3 = 60 mg TRY
adult RDA = 6.6 NE/1000 kcal
not < 13 NE
typical US diet = 16-34 NE/day

Biochemical Functions of B-3
Oxidation-Reduction Reactions
Dehydrogenases
Electron Transport System
Synthetic Pathways (NADPH)

Deficiency of B-3
Pellegra
Dermatitis
scaly dermatitis, sun exposed
Dementia
confused, disoriented
Diarrhea
irritation/inflammation of mucous membranes

Assessment of B-3 Status
Urinary excretion of niacin metabolites
N-methyl nicotinamide
2-pyridone

Niacin Toxicity
1-3g/day for treatment of hypercholesterolemia
increases histamine release
skin flushing
increase risk of peptic ulcers
liver injury
time release forms greater risk of liver injury

Folic Acid / Folacin
Structure
pteridine ring - PABA - glutamate
Stability
very sensitive to heat
easily oxidized
leached

Digestion & Absorption
dietary form: polyglutamyl folate
glutamate gamma linked
Folate conjugase
Zinc deficiency
alcoholism
drug interactions
folate absorbed as monoglutamate

Folate Metabolism
Intestinal Cells
folate reduced to tetrahydrofolate
folate reductase
inhibited by methotrexate
methylated to N5-methyl-THF
primary blood form

Folate Functions
Single carbon metabolism
N5-methyl      -CH3
N5-formyl      -CH=O
N5-formimino  -CH=NH
N5N10-methylene  -CH2-

Folate Functions
Interconversion of serine and glycine
ser + THF <---> gly + 5,10-Me-THF
Degradation of histidine
his->->->formiminoglutamate(FIGLU)
FIGLU+THF -> glu + 5-forminino-THF
histidine load test

Folate Functions
Purine and Pyrimidine Synthesis
dUMP + 5,10-Me-THF -> dTMP + THF
Methionine Synthesis
homocysteine + 5-Me-THF -> MET + THF
MET as a methyl donor for choline synthesis

Folate Deficiency
Megaloblastic Anemia
decreased DNA synthesis
failure of bone marrow cells to divide
normal protein synthesis
results in large immature RBC’s
contrast with microcytic hypochromic anemia

Folate Deficiency
Homocysteine
Coronary Heart Disease risk factor ?
genetic homocystinuria - premature CHD
hi [homocys] related to hi CHD risk
lo [folate, B-12, B-6] related to hi CHD risk
lo intake of B-vit related to hi CHD risk

Folate and CHD
Nurse’s Health Study (JAMA 1998)
80,000 nurses, 14 yr follow-up
Relative Risk - highest vs lowest quintile
RR = 0.69 for folate
RR = 0.67 for B-6
RR = 0.55 for folate + B-6

Folate and Neural Tube Defects
Defects in formation of neural tube (brain & spinal cord)
First two months gestation
Anencephaly
absence of cerebral hemispheres

Folate and Neural Tube Defects
Spina bifida
defective closure of vertebral column
spinal cord protrusion from spinal column
lower limb and hip paralysis
rectal and bladder problems

NTD Prevalence
US:
4000 live births with NTDs/yr
1/1000 pregnancies
World:
400,000 live births with NTDs/yr

NTDs and Folate
NTDs associated with mothers with low blood [folate]
Estimated that 50% of NTDs prevented with folate supplementation w/ 200 ug/d
DRI adults = 400 ug/d
DRI prenancy = 600 ug/d
typical US intake = 280-300 ug/d

Folate and Grain Enrichment
Jan 1, 1998
140 ug/100g enriched grain
results in additional 100 ug/d
may reduce about 25% of NTDs
limited because of masking of B-12 deficiency

Vitamin B-12
Structure
cobalamine
methyl cobalamine
transport and coenzyme form
adenosyl cobalamine
storage and coenzyme form

Dietary Sources
Animal products
including milk and eggs
GI microorganisms
Vegan sources
N-fixing legumes
fortified grains
vitamin supplements

Digestion & Absorption of B-12
Protein bound in foods
released by acid and pepsin
elderly
R-protein
gastric secretion
binds with free B-12
protects B-12 from bacterial use ?

Digestion & Absorption of B-12
Intrinsic Factor
gastric glycoprotein
binds with B-12 in small intestine
IF-B-12 complex binds to B-12 receptor in ileum for absorption
B-12 absorption requires functioning stomach, pancreas, and ileum

Causes of B-12 Deficiency
Inadequate intake - rare
DRI adults 2.4 ug/d
Usual intake 7-30 ug/d
Malabsorption of B-12
IF deficiency
other GI tract problems

Shilling Test for Malabsorption
Saturation of B12 by injection
Oral administration of radiolabeled B12
free B12
IF-B12
Measure urinary excretion of labeled B12

Functions of B12
Homocysteine to Methionine
methionine synthetase
requires 5-methyl THF
deficiency of B12 results in “methyl-trap” of folate
results in megaloblastic anemia
synergistic effect of B12 and folate

Functions of B12
Mutases
methyl malonyl CoA mutase
proprionyl-CoA ->->succinyl-CoA
accumulation of methyl-malonate may inhibit AcetylCoA carboxylase

B-12 Deficiency
Pernicious anemia
megaloblastic anemia (folate trap)
neuropathy
defective myelination
progressive peripheral weakening
unresponsive to folate
upper limit to folate supplementation/enrichment

Vitamin C - Ascorbic Acid
Structure
Metabolism
oxidation/reduction
dehydroascorbic acid
dehydroascorbate reductase
glutathione (GSH)
glutamate-cysteine-glycine

Functions of Vitamin C
Hydroxylation Reactions
Involves O2 and metal coenzyme
(ferrous, cuprous)
Carnitine synthesis
Tyrosine synthesis & catabolism

Functions of Vitamin C
Hydroxylation of proline and lysine
post-translational reaction of procollagen
hydroxylated collagen can be cross-linked to triple helix collagen
Scurvy - weak collagen

Functions of Vitamin C
Synthesis of Neurotransmitters
Dopamine
Norepinephrine
Serotonin
Bile acid synthesis

Functions of Vitamin C
Enhances absorption of iron
reduces iron to more absorbable ferrous form
chelates with ferrous ion to make it more soluble

Functions of Vitamin C
Antioxidant Activity
Reacts and removes active oxygen species
Pro-oxidant Activity
Reduces metals to their pro-oxidant forms

Scurvy
Bleeding gums
petechiae
easy bruising
impaired wound healing and bone repair
joint pain
anemia

RDA for Vitamin C
10 mg/day prevents scurvy
historic RDA’s 45-70 mg (60mg in 1989)
prevention of scurvy vs antioxidant effect with supplements?

Toxicity of Vitamin C
Osmotic diarrhea
Oxalate kidney stones
Decreases uric acid reabsorption resulting in increased risk of gout
Affects diagnostic tests in feces and gout
fecal blood
urinary glucose

Oxidant Tissue Injury and Nutritional Antioxidants
Dr. David L. Gee
NUTR 443 - Nutrition II

Oxidant Tissue Injury
Controlled Oxidation of Substrates
Energy generation
glycolysis
B-oxidation
TCA cycle
ETS

Oxidant Tissue Injury
Uncontrolled Oxidation of Tissue Components
Random oxidation initiated by oxygen free radicals

Free Radicals
compounds containing an unpaired electron
highly reactive
removes electrons from other compounds and thereby oxidizes them

Short Term Oxidative Injury
Trauma
Infection
Radiation
Toxins
Intense Exercise
Reperfusion (following MI & stroke)

Long Term Oxidative Injury
Coronary Heart Disease
oxidized LDL-C
Cancer
initiation, promotion, progression
Aging

Sources of Oxygen Radical
10,000 oxidative “hits”/day
Mitochondrial electron transport
extreme exercise
Microsomal cytochrome P-450 system and mixed function oxidase system
metabolism of foreign chemicals

Sources of Oxygen Radical
Enzymes producing H2O2
xanthine oxidase
D-amino acid oxidase
High energy radiation
Environmental sources
cigarette smoke
ozone
nitrogen oxides

Mechanism of Injury
Membrane damage
Lipid Peroxidation
Unsaturated fatty acids
Potential chain reactions
Lipid cross-linking
Lipid - protein cross linking
Oxidative damage to protein and DNA

Nutritional Antioxidants
Antioxidant Vitamins & Chemicals
vitamin E
ascorbic acid
carotenoids
plant phytochemicals

Nutritional Antioxidants
Antioxidant Enzymes
Catalase (Fe)
Glutathione Peroxidase (Se)
Superoxide Dismutase (Zn, Cu)

Vitamin E
Tocopherols
D-alpha-tocopherol
RRR-alpha-tocopherol
natural, highest antioxidant potential
DL-alpha-tocopherol
all-rac-alpha-tocopherol
synthetic, less potent

Vitamin E
Tocopherols
beta-tocopherol
gamma-tocopherol
Tocotrienols
Function of Vitamin E
Major lipid soluble antioxidant
Protects membranes from lipid peroxidation
Free-radical scavenger

Deficiency of Vitamin E
Rare, associated with fat malabsorption
hemolytic anemia
Premature infants
poorly transported thru placenta
treatment w/ O2 & Fe
retinopathy

Vitamin C
Major water soluble antioxidant
direct scavenger of free radicals
may be involved in the regeneration of
 vitamin E
glutathione

Carotenoids
Pigments found in plants and microorganisms
~ 600 identified compounds
< 10% synthesized into vitamin A
Primary Forms in Human Tissues
Beta carotene
alpha carotene
lycopene
lutein
beta-cryptoxanthin

Metabolism of Carotenoids
Major dietary sources: fruits and vegetables and tomato sauces (lycopene)
Avg US intake 6 mg/day
Low absorption rate (10-30%)
Some converted to vitamin A in intestinal cell
Most transported in chylomicrons

Metabolism of Carotenoids
Adipose primary storage depot
Carotenoids are not toxic
low plasma levels associated w/
body mass
smoking
alcohol intake

Biological Functions
Vitamin A precursers
Quenchers of singlet oxygen
Free radical scavenger
Lycopene may be a superior antioxidant than B-carotene and lutein
Less carotenoid in LDL than Vitamin E

Antioxidant Enzymes: Catalase
2H2O2  --> 2H2O + O2
 contains heme iron

Antioxidant Enzymes: Glutathione Peroxidase
Contains selenium
2H2O2 + 2GSH --> 4H2O +  GSSG
LOOH + 2GSH --> LOH + H2O + GSSG
Se deficiency causes muscle injury
nutritional muscular dystrophy in animals
cardiac myopathy in humans

Antioxidant Enzymes: Superoxide Dismutase
Copper & Zinc containing enzyme
removes superoxide radicals
2O2- + 2H+ --> H2O2 + O2

Mineral Toxicity
symptoms can occur at 10X RDA
Selenium
nausea, vomiting, neuropathy
Zinc
interfers with Cu absorption
GI irritation
anemia, fever, CNS disturbances
Copper ?

Evidence Supporting Use of Antioxidant Supplements
Epidemiological Studies
Generally show correlations between intake of antioxidants & plasma levels of antioxidants with lower risk of certain cancers and heart disease.
Evidence Supporting Use of Antioxidant Supplements
Animal Studies
Generally shows that antioxidant supplements decrease oxidative tissue injury.
Evidence Supporting Use of Antioxidant Supplements
Human in vitro studies
Generally shows that antioxidants reduce oxidant tissue injury or oxidant risk factors associated with heart disease and cancer.
Evidence Supporting Use of Antioxidant Supplements
Human Intervention Trials
Mixed results
some show benefits
some show no effects
some show negative effects
carotenoids, smokers, lung cancer

Vitamin A
David L. Gee, PhD
NUTR 443 - Nutrition II
Chemistry
Animal forms
retinal
retinol
retinoic acid
Plant precurser forms
carotenoids
B-carotene

Stability
Susceptible to oxidation
Susceptible to UV light destruction
Relatively heat stable

Digestion and Absorption
Retinoids
70-90% absorbed
Carotenoids
20-50% absorbed
intestinal carotene dioxygenase if low in vitamin A
Transport vit A ester in chylomicron
Storage of vit A ester in liver (kidney, adipose)

Transport of Mobilized Vitamin A
Retinol Binding Protein
Indicator of protein deficiency or liver disease
toxicity occurs when retinol exceeds binding capacity of RBP

Function: Visual Cycle
Retinal - active form
Rhodopsin - retinal containing protein required for rod cell function
Constant supply of retinal required for rod cell function
Early sign of vitamin A deficiency - night blindness, poor dark adaptation

Hormonal Activity of Retinoic Acid
Most vit A is stored as retinol (ester)
Oxidation of retinol to retinoic acid is limited and tightly regulated
Certain genes have a retinoic acid receptor
Binding of retinoic acid to RAreceptors activate the gene

Hormonal Activity of Retinoic Acid
RA induces the differentiation of cells, controlling which genes are turned on an off
RA induces synthesis of glycoproteins in mucous secreting epithelia cells

Vitamin A Deficiency
Night blindness
Keratinization of epithelial cells
Xeropthalmia
Intestinal malabsorption
Decreased disease resistance
Abnormal bone development
Impaired reproduction

RDA for Vitamin A
IU = 0.3 ug retinol = 1.8 ug B-carotene
RE = 1 ug retinol = 6 mg B-carotene
RE = 3.33 IU retinol = 10 IU carotenoids
RDA = 800-1000 RE/d

US Intake of Vitamin A
RDA = 800-1000 RE/d
Avg US intake =  900 RE/d
Avg US intake of carotenoids = 1.5 mg/d
NCI rec intake of carotenoids = 5-6 mg/d

Vitamin A Toxicity
Headache, nausea, vomiting
double vision, drying of skin & mucous
irritability, anemia
teratogenic
toxicity as low as 2000 RE/d
most studies at 5000-20,000 RE/d
supplements at 4500RE (15,000 IU)
 

Minerals

Iron

Iron Distribution & Function
Functional Iron
Hemoglobin - 70%
Myoglobin - 3%
Cytochromes & Catalase - 0.2%
Storage & Transport Iron
Ferritin & Hemosiderin - 26%
Transferrin  - 0.1%

Prevalence of Iron Deficiency
Iron deficiency anemia
Worldwide
second most common nutritional deficiency
USA
American diet - 6 mg/1000 Cal
RDA males 10 mg/d (need 1700 Cal)
RDA females 15 mg/d (need 2500 Cal)

Groups at Risk for Iron Deficiency
Infants < 2yrs
hi growth, hi tissue concentration
Young women
growth, mentrual blood loss, poor diets
Pregnant women
growth, blood volume
Elderly
poor diets, low absorption

Iron Absorption
Tissue levels of iron regulated here
primarily in duodenum
heme iron
absorbed intact into enterocyte
Fe+2 enzymatically removed and combines with apoferritin
non-heme iron
absorbed into enterocyte, combines with apoferritin, 1/2 -1/5 as well absorbed as heme iron

Iron Absorption
Enterocyte ferritin stores iron and transports it to basolateral membrane
A regulated ATP-dependent transport protein moves Fe+2 to blood
Fe+2 transported attached to transferrin
Absorption regulated by transferrin saturation (normal 30-35%)

Factors Affecting Iron Absorption
Factors increasing iron absorption
vitamin C
iron deficiency
“meat factor”
lactoferrin (breast milk)
Factors decreasing iron absorption
phytates, tannins
oxalates
achlorhydria

Iron Storage
Ferritin & hemosiderin
30% liver
30% bone marrow
40% muscle and spleen

Iron Losses
Iron is highly conserved, 10% lost per day through bile
Blood loss
menstrual blood loss
hemorrhage
blood donation

Iron Deficiency
Stage I - Iron Depletion
depletion of stores
low plasma ferritin
no functional impairment
Stage II - Iron Deficient Erythropoiesis
transferrin saturation < 16%
RBC protoporphyrin elevated
hemoglobin near normal
work capacity?

Iron Deficiency
Stage III - Iron deficiency anemia
microcytic
low mean corpuscular volume
hypochromic
low hemoglobin
fatigue, lethargy

Iron Toxicity
Causes:
excess iron intake
transfusion overload
acute toxicity
hereditary excessive iron absorption
Accumulation of hemosiderin
insoluble saturated ferritin
liver

Iron Toxicity
Hemosiderosis
accumulation of hemosiderin
Hemochromatosis
hemosiderosis + tissue injury
liver & pancreas
weakness, fatigue, achy joints

Assessment
serum ferritin
transferrin saturation
Excess Iron and Heart Disease
Finnish epidemiological study
2000 adult men
1% increase in ferritin caused 4% increase in heart attack risk
iron intake and ferritin levels in Finns significantly  higher than Americans
High iron increases oxidation of LDL
1/250 US men with hemochromatosis
% w/ hemosiderosis?

Prevention of hemosiderosis
No iron supplements in needed for men or post-menopausal women
Screening for serum ferritin?
Family history
Blood donation for hemosiderosis