Metabolism Part 3 Flashcards
What cleaves sucrose in the intestine?
Sucrase-isomaltase
What does loss of Sucrase-isomaltase cause?
Osmotic-fermentative diarrhea
What gets Fructose into the enterocyte?
GLUT5
Does GLUT5 saturate?
Yes, quickly
but fructose is inducible
What transporter does Fructose use to enter the blood from the enterocyte?
Mostly GLUT2 (some GLUT5)
What does Fructose get converted into in muscle?
Fructose-6-Phosphate
same as glucose
What enzyme phosphorylates fructose in the liver?
Fructokinase
What enzyme is skipped in the fructose pathway in the liver?
What enzyme is used instead?
PFK-1
Fructose-1-phosphate aldolase
aka ALDOLASE B
Does fructose need insulin to enter the cell?
no
What does the lack of PFK-1 cause in fructose metabolism?
Uncontrolled manufacture of Acetyl CoA and Citrate
T/F
Excessive dietary intake of fructose may lead to decrease in available Pi
True
The decrease of ATP in the cell due to fructose consumption caused by lack of available phosphate causes what?
Breakdown of residual ADP and AMP
results in hyperuricemia and gout
What is the slow step in fructose metabolism?
Fructose-1-phosphate aldolase
aka Aldolase B
Fructokinase pathologies tend to be ______, while Alsolase B (Fructose-1-phosphate aldolase) pathologies tend to be ________.
Benign
Severe
What is the first step metabolite of Fructose in the muscle?
The liver?
Frc-6-P
Frc-1-P
What does Mannose (after 2 steps) metabolize into?
Fructose-6-P
What rxn traps glucose in a cell without committing an ATP?
Glc - Sorbitol
What cells build up sorbitol during hyperglycemia?
Cells that store sorbitol (after conversion from glc) and can’t convert that into Fructose
What are the effects of too much sorbitol?
Osmotic effects and swelling
What happens to galactose when it enters the cell?
What is the main substrate here?
Galactose is broken down (first by Galactokinase) in 4 steps to G-6-P.
UDP-galactose-4-epimerase
Once galactose has a UDP power pack on, what are its options?
Can enter glycolytic pathway or GNG
What 3 (main) parts of the body are affected by fluctuations in Calcium concentration?
neurological
gastrointestinal
renal
What is necessary for the absorption of dietary Calcium in the intestine?
Vitamin D
What is the main source of stored Calcium in the body?
Hydroxyapatite
Ca10(PO4)5OH2
What does lack of Calcium (hypocalcenemia) cause?
Tetany (contractions)
What is the most concentrated protein in the blood?
Name two things it carries.
Serum Albumin
Fatty Acids (SCFA, MCFA) Calcium
T/F
If Serum Albumin levels are abnormal, calcium can’t be calculated
False
What corrects the measurement of Calcium if Serum Albumin are off?
Corrected Calcium (equation)
What are the 3 main areas that maintain calcium homeostasis?
Gastrointestinal tract
Kidney
Bone
How much calcium goes into bone every day?
How much comes out?
500 mg
500 mg
What are the 2 types of ways calcium moves out of the lumen?
Transcellular transport (duodenum)
Paracellular (jejunum and ilium)
What type of transport out of the lumen is increased if calcium intake is low?
Transcellular (this can be controlled)
Why does Vitamin D deficiency often lead to Calcium deficiency?
poor absorption without Vita D
What are 3 foods that absorb calcium in the gut and prevent Vitamin D from doing its job?
rhubarb, spinach, and chard.
What are the main hormones that reciprocally regulate calcium?
PTH, Calcitonin, and Vitamin D
Vitamin D is a hormone
UV light hits cholesterol to make?
How is this activated?
Cholecalciferol
2 Hydroxylations to form Calcitriol
(aka 1,25 dihydroxycholecalciferol)
The key enzyme in Vitamin D activation controlled by PTH levels is?
1-Alpha-Hydroxylase
Where do the 2 hydroxylations that create activated Vitamin D occur?
Liver (1st hydroxylation)
Kidney (2nd hydroxylation forming Calcitriol)
What molecule, under the direct control of Vitamin D, mediates the transport of Calcium across the enterocyte (apical to basolateral)?
Calbindin-D9k
What is the rate limiting step of calcium transport?
Calbindin-D9k moving Calcium across the enterocyte
What 2 ways does Calcium enter the blood from the enterocyte?
via an ATP pump
(1 Ca++ out / 2 H+ in)
Na+/Ca++ exchanger
(3:1)
What often mediates intracellular calcium?
Are these under the control of Vitamin D?
Troponin C (muscle) Calmodulin (other cells)
*theses are calcium binding proteins
What has greater effects, PTH or Calcitonin?
PTH
Where is Calcitonin produced?
How long is the polypeptide?
Parafollicular (C) cells of Thyroid
32 AA and linear
T/F
Transcellular transport of Calcium is regulatable, while Paracellular is not.
True
Where does Paracellular transport take place?
Across tight junctions
and down the concentration gradient
What 3 things does Calcitriol (Vita D) control in the enterocyte?
Transporters on luminal (apical) side
Transporters on basolateral side
Calbindin (which takes it across the cell)
What are the epithelial Calcium channels called that go from lumen to enterocyte?
TRPV5 and TRPV6
What is the main cause of Hypocalcemia?
Vitamin D deficiency
rickets!
What are the 2 main counter regulatory hormones to insulin?
Glucagon
Epinepherine
Name 5 catabolic compounds that counter the action of insulin:
Glucagon Epinepherine Norepinepherine Cortisol Growth Hormone
What is the rate limiting step of Epinepherine synthesis and release?
What is the rxn?
Tyrosine Hydroxylase
Tyrosine > Dopa
Where does the rate limiting step of epinepherine synthesis occur?
Adrenal Medulla
chromaffin cells
What type of membrane transduction does epinepherine work through?
GPCR
G-Protein compound receptor
What are epinepherine’s effects in the:
pancreas?
adipose?
Pancreas - inhibits insulin release and stimulates glucagon release
Stimulates lipolysis
What are epinepherine’s metabolic effects in the liver and muscle?
Liver: increase GNG
Muscle: increase glycolysis
What is produced at the islets of Langerhans?
Glucagon - by the Alpha cells
Insulin - by the Beta cells
also, Somatostatin by the Delta cells
T/F
The pancreatic hormones have only endocrine effects.
False
also have local autocrine and paracrine effects
What is given to diabetics to counteract hypoglycemia?
Glucagon
What is Proglucagon broken down into in the pancreas and in the intestine?
pancreas: Glucagon
intestine: GLP-1 (and also GLP-2 and Oxyntomodulin)
What is the major target of Glucagon?
What is the mechanism to enter the cell?
Liver
G-protein second messengers
What are glucagon’s effects on:
glycogen phosphorylase
glycogen synthase
PFK-1?
increase
decrease
decrease
What are glucagon’s effects on:
Frc-1-6-BP
Pyruvate kinase
Triacylglycerol lipase
increase
decrease
increase
Insulin has 1/2 life of 5 minutes. How can we more easily measure insulin release clinically?
C-peptide from the “Prepro” hormone
Describe insulin’s effects on target cells.
Insulin binds outside
Tyrosine Phosphorylated
After phosphorylation, what is the most important downstream effect of Insulin binding?
Translocation of GLUT4 to the membrane
this allows Glc to enter cell
What is one of the effectors of GLUT4 inside the cell after Insulin binding?
P13-kinase
T/F
Insulin features prominently in the uptake of ions such as K+ and PO4-3.
True
What senses glucose in the pancreas?
GLUT2 (ferrari)
Glucokinase
What is the pathway leading to insulin release at a Beta cell?
Glc enters through GLUT2 Glycolysis creates ATP ATP shuts down K+ channel depolarization opens Ca++ channel Calcium stimulates insulin release
What is the insulin and glucagon response following a high carbohydrate meal?
a high protein meal?
carb: Insulin up, glucagon down
protein: Insulin AND glucagon up
What 3 Amino Acids stimulate the release of Insulin?
AGR
alanine
glycine
arginine
How do A, G, and R AA’s depolarize Beta cells?
Alanine & Glycine - Na+ symport depolarizes
R (arginine) - dedicated transport protein. Arg is a cation and depolarizes cell directly
What class of substances is responsible for the greater insulin response when taken orally?
Incretins
remember: GLP-1 and the Gila monster
What is the coenzyme in catecholimine rate limiting step?
epinepherine
Tetrahydrobiopterin > Dihydrobiopterin
What is the function of GLP-1 in the liver?
remember: this comes from Proglucagon
Enhances Insulin effects
also Gila monster drug - (Incretins)
What are the body’s priorities after a meal?
- Replenish glycogen stores
- store fat
- increase protein reserves
What are the body’s 2 biggest goals when hungry?
- Brain and CNS (GNG, etc)
2. Conserve protein
What are the 2 main sources of fuel during fasting (1 hr after meal)?
Liver glycogenolysis - glc
Adipose Lypolysis - fat
In a progression of fasting (beyond a few hours), what does the liver also make (besides breaking down glycogen)?
GNG pathways are activated
If a fast continues for 2 or more days, what occurs in the muscle and brain?
Muscle switches off ketone bodies (oxidizes fatty acids) so they can go to the brain.
When is glc not the sole fuel for the brain?
prolonged starvation
Why does skeletal muscle produce lactate when actively contracting?
Glycolysis much faster than CAC so buildup of product.
What does resting muscle preferentially metabolize?
Fatty acids
T/F
Heart has glycogen reserves
false
What is the main source of fuel for the heart?
fatty acids
ketone bodies/lactate CAN fuel the heart
What is the glycolytic intermediate in adipose tissue necessary for synthesis of TAG’s?
(somehow leads to CoA derivative transfer to glycerol-3-P)
dihydroxyacetone phosphate
Why are Fatty Acids released into the blood if glucose levels are low?
No glycerol-3-Phosphate for TAG synth
What organ provides half GNG during starvation?
Kidney
What are the main precursors to GNG in liver?
Lactate and Alanine from muscle
glycerol from adipose
glucogenic AA’s from diet
What does the liver make ketone bodies out of in the fasting state?
Fatty Acids
What prevents Fatty acids from entering the mitochondrial matrix?
Malonyl CoA
this is fed state and FA’s exported to adipose
What allows the passage of Fatty Acids into the mitochondrial matrix to make ketone bodies under low energy conditions?
Low levels of Malonyl CoA
The liver absorbs most of the AA’s from the blood. What is the priority for use?
Protein synthesis
rather than catabolism
What three AA’s are processed in muscle rather than liver?
Leucine, Isoleucine, and Valine
LIV
What does the liver use as its main energy source?
Alpha-Ketoacids
glycolysis are building blocks and ketogenics are exported
Does Adipose tissue undergo Beta-oxidation?
Negative
exports FA’s for breakdown in other tissues
T/F
Glucagon inhibits Insulin (but not vise versa)
FALSE
Insulin inhibits glucagon
Glucagon does not inhibit insulin
(if glucagon levels are high reasonable to assume meal is just around the corner)
How long do glycogen stores last?
12-18 (maybe 24) hours
What does muscle preferentially use for energy if Glucagon is high?
FAT
What does skeletal muscle use for energy in the first few days of not eating?
Fat, Ketone bodies (reach highest level at Day 3), Fat
this allows ketone bodies to go to the brain
(GNG decreases and spares muscle)
What 2 energy sources remain constant in fasting Day 3 to 40?
Adipose lypolysis
Ketone body formation
Why does urea excretion go down with prolonged fasting?
Preserve water and muscle (as much as possible)
Why does the liver lag in the uptake of Glc after a meal?
leaves it for peripheral tissues
stays in GNG mode for glycogen synth
What is the Master Switch (energy sensor enzyme)?
What activates?
What does it do?
AMPK
high levels AMP
produces ATP (and shuts down processes using ATP)
What, specifically, does AMPK do?
phosphorylates rate-limiting enzymes in energy using/producing pathways
(senses cellular energy levels)
Define:
polyuria
polydipsia
polyphagia
Lots of urine
thirsty
hungry
What part of insulin can be detected longer?
C-peptide
What lipid enzyme does insulin stimulate?
Acetyl CoA Carboxylase
Why are you sleepy after a meal?
Insulin actually makes blood slightly hypoglycemic
Frequency of Ketosis in Type 1 vs Type 2 diabetes?
Type 1 - common
Type 2 - rare
Why is Type 1 diabetes unresponsive to oral drugs treating hypoglycemia?
No insulin whatsoever
What cells are totally eliminated (eventually) in Type 1 diabetes?
Beta cells
What cell receptor needs insulin for fat uptake?
Lipoprotein Lipase
What two states characterize type 2 diabetes?
insulin secretion deficit
insulin resistance
The curve of insulin output in Type 2 diabetes is due to:
Burnout of Beta cells
Why is ketoacidosis less of an issue with Type 2 diabetes?
There’s still a little insulin
How is hyperglycemia measured?
Hemoglobin A1c
What 3 conditions must be met for sorbitol to do real damage?
- Diabetic
- tissue must be able to take up glc without insulin
- tissue lacks ability to take sorbitol to fructose
What enzyme makes sorbitol from glucose?
Aldose reductase
What comprises metabolic syndrome?
Hyperglycemia
low HDL
Apple fat
high TAG’s
Preproinsulin is synthesized in the:
Proinsulin breaks down to Insulin and C-peptide in the:
ER
Golgi
What makes up insulin structurally?
Alpha and Beta chains attached by two disulfide bonds
What type of adipocytes are more hormonally responsive and have a greater impact on the liver?
Abdominal
What receptor increases with the amount of fat you store?
Lipoprotein Lipase
note: this sticks around after losing weight so more efficient at storing fat
Obesity is a disease of chronic…
Inflammation
Name 3 Adipokines that increase with obesity and one that does not.
Leptin, TNf-alpha, IL-6
Adiponectin
What two Adipokines induce insulin resistance?
TNF-alpha
IL-6
Does leptin increase with weight?
It should be proportional to adipose tissue.
What does a lot of leptin signal?
What does low levels of leptin signal?
Leptin signals the brain and tells you you’re full, so low amounts signals to slow down, don’t eat, stay on the couch.
What suggests human obesity isn’t related to the amount of Leptin?
Trials negative (positive with mice and that kid in Turkey)
This suggests the brain’s resistance to Leptin
What adipokine decreases inflammation?
Adiponectin
What structure in the brain is responsible for integrating hunger/satiety signals?
Hypothalamus
What structure in the brain is associated with overeating and obesity?
Damage to
Ventromedial or
Paraventricular nuclei
(VM and P of the hypothalamus)
What part of the hypothalamus is often damaged in weight loss and anorexia?
Lateral Hypothalamic
What two types of neurons in the hypothalamus regulate appetite?
Orexigenic (go eat)
Anorexigenic
Name 2 Orexigenic neurons:
Neuropeptide Y (NPY) Agouti related protein (AgRP)
(these nerves signal the proteins they’re named for)
What are the two Anorexigenic neurons in the hypothalamus?
One has an important derivative:
POMC (pro-opiomelanocortin)
CART (cocaine/amphetiamine regulated transcript)
note: POMC processed to alpha-MSH (melanocyte stimulating hormone)
What does Leptin stimulate and inhibit in the hypothalamus?
stimulates anorexigenics:
POMC/MSH
inhibits orexigenics:
NPY/AgPR
What acts in a similarly to Leptin in the hypothalamus?
Insulin
can’t go far wrong thinking Insulin and Leptin do the same thing
Name 2 molecules in the intestine that act as satiety signals to the brain?
CCK
GLP-1
(note: GLP-1 signals brain and pancreas)
What are the functions of GLP-1?
acts as satiety signal to the brain
incretin for insulin and pancreas
(increases insulin secretion, biosynth, B-cell proliferation, B-cell survival)
What is the peptide hormone that acts as an appetite stimulant originating in the stomach?
What are its actions on the brain?
Ghrelin
binds/stimulates NPY/AgPR/GABA neurons
(orexigenic = glucagon-like)
Under normal circumstances what occurs in cells in response to weight gain?
Cells grow larger (hypertrophy)
Under what circumstances do we see new adipocytes forming instead of just increasing in size?
Severe obesity
Where is alcohol generally oxidized?
80-90% in the liver
What part of the GI tract absorbs alcohol?
What part is most effective?
All parts small intestine (because of large surface area)
Does alcohol require a transporter to enter cells?
NO
T/F
15% alcohol eliminated in sweat, urine, feces, breath, saliva, and lactation.
False
10%
What is the main enzyme used by “naive” alcohol consumption?
Where does this occur?
Alcohol dehydrogenase
Cytosol
What system is used in habitual drinkers to metabolize alcohol?
Where does this take place?
Cytochrome P450
(MEOS)
Smooth ER
What are the major and minor routes of ethanol oxidation?
Major:
Alcohol dehydrogenase in cytosol
Cytochrome P450 (MEOS) in Smooth ER
Minor:
Catalase dependent oxidation in Peroxisome
Gastric Oxidation (first pass) in stomach
What do the metabolic routes of ethanol processing have in common for both habitual and “naive” drinkers?
Both seriously deplete NAD+
dehydrogenase =
redox
What are the two main steps of ethanol metabolism?
Where do they occur?
cytosol:
Ethanol > Acetaldehyde
(Alcohol dehydrogenase)
mitochondria:
Acetaldehyde > Acetate
(Aldehyde dehydrogenase - ALDH2)
Why is acetaldehyde damaging to the cell?
creates many adducts
increases ROS
What does ethanol consumption do to the following rxn:
pyruvate + NADH > lactate + NAD+
Le Chat pushes toward lactate due to 10 fold increase in NADH
What is the product Acetate (from ethanol met.) converted into?
Acetyl CoA
*requires GTP
Cytochrome P450 aka:
CYP2E1
What can ROS/Acetaldehyde from ethanol metabolism damage?
proteins
causes lipid peroxidation
Mutagenic/Carcinogenic
DNA repair
What cofactor does Alcohol Dehydrogenase carry?
Zinc metalloprotein
How many genes code for how many classes of Alcohol Dehydrogenase and which one has the lowest Km?
7 genes
5 classes
lowest Km (highest affinity) is Class I in the liver *this is the major one
What is a major contributor to the variation we see in ability to metabolize alcohol?
ALDH2 variants
Pretty much all the biochemical downstream side effects of ethanol ingestion is due to:
Decreased NAD+/NADH ratio
Why does alcohol cause hypoglucemia?
excess NADH prevents GNG in liver
What are 4 major consequences of decreased NAD+/NADH ratio?
Hypoglicemia (GNG suppressed)
Lactic Acidemia
Ketonemia (lots Acetyl CoA, no glycogen, no GNG)
Hyperuricemia (ketones/lactate compete with uric acid for renal pump)
Why does alcohol cause dehydration?
inhibits ADH
How does alcohol affect protein trafficking?
4 ways
Fatty liver (acetaldehyde adducts tubulin)
Protein secretory/plasma mem. assembly impaired
VLDL export decreased
*receptor mediated endocytosis affected
What does alcohol consumption do to the major excitatory and inhibitory neurotransmitters?
Inhibits Glutamate (excitatory) - uncoordination, speech, memory
Enhances GABA (inhibitory) - anxiety reduction and sleep
Are most alcoholics malnourished?
no
What 3 vitamin deficiencies do alcoholics often have?
Thiamin (B1)
Folic Acid
Vitamin A
What syndrome is associated with decreased thiamin levels due to alcohol consumption?
Wernicke-Korsakoff syndrome
Folic acid depletion leads to…
anemia
Why is Vitamin A deficiency seen upon alcohol consumption?
Retinol (Vitamin A) degraded by MEOS
resembles alcohol just enough
T/F
Alcohol has a greater overall effect on women
True
Which vitamins are water soluble?
B and C
total of 9
What are the fat soluble vitamins?
ADEK
What is the most important Vitamin?
D
*calcium and bloot clotting
What is Vitamin A important for?
growth, immune system, vision
What is Vitamin C important for?
Collagen/scurvy
*hydroxylation step in collagen synth
Vitamin B1:
name
pathology
Thiamine
Beriberi, Wernicke Korsikoff
Vitamin B2
name
pathology
Riboflavin
mouth lesions and dermatitis
B5
name
pathology
Pantothenate
Hypertension
B6
name
pathology
Pyridoxal phosphate (*aminotransferases)
Depression, confusion, convulsions
B7
name
pathology
Biotin
rare rash/fatigue
B9
name
pathology
Folate
anemias
B12
name
pathology
Cobalmin
anemias
(*Odd Homo Meth)
B3
name
pathology
NAD - Niacin
Pellagra (dermatitis, depression, diarrhea)
Vitamin A
name
pathology
Retinol
Night blindness
Vitamin D
name
pathology
Calcitriol
Rickets, osteomalacia
Vitamin E
name
pathology
tocopherol
Erythrocyte hemolysis (newborns)
Vitamin K
function
pathology
synth prothrombin and clotting factors
difficulty in blood coagulation (takes a long time)
