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Pathobiochemistry > Flash Cards for PathoBiochem > Flashcards

Flash Cards for PathoBiochem

1
Q

What factor is released by

cells during hypoxia

A

HIF-1 hypoxia and factor 1

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2
Q

What are some genes

regulated by HIF-1

A

GLUT1 GLUT3 Growth factors. VEGF IGF2 Glycolysis enzymes

Phosphofructokinase Hexokinase Lactate dehydrogenase

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3
Q

What diseases does hypoxia

play a pathogenic role?

A

Ischemia… COPD Malignant tumors Atherosclerosis Diabetes

mellitus Inflammatory diseases Psoriasis Pre-ecllampsia

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4
Q

How are ROS generated?

A

By the incomplete reduction of oxygen (O2)

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5
Q

What are the categories
disorders of major
homeostasis? (6)

A

Oxygen Redox and antioxidant Immunohomeostasis Cell volume

regulation pH homeostasis Hemostasis

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6
Q

Functions of the ER

A

Protein synthesis Lipid synthesis Biotransformation Ca++ storage
Production of glucose Protein synthesis for secrion, ER secretory
pathway Heme synthesis

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7
Q

Potential responses to

organelle stress

A

Adaptation Unfolded protein response (ER response)

Mitochondrial Stress response Death Apoptosis Necrosis

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8
Q

ammonia plasma concedntration

A

15-50 uM

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9
Q

4 ways ammonia can cross a cell

membrane

A

It can take the place of Potassium in either: Na/K ATPase Na K
2Cl symporter It can replace Hydrogen in the Na/H antiporter
It can move through Aquaporins at low effeciency Rhesus
glycoproteins, specific ammonia transporters, in the kidney

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10
Q

How can ammonia be produced?

A

De amination of Cytosine, Adenine, or Guanine De amidation
of glutamine or asparagine Glutaminase Oxidative de
amination of Glutamate By glutamate dehydrogenase
Oxidative deamination of any amino acid to an alpha-ketoacid

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11
Q

Which amino acid is deaminated

to make adenosine?

A

Aspartate, via an adenylosuccinate intermediate

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12
Q

What amino acid transports

ammonia from the muscle to the liver?

A

Glutamine and Alanine

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13
Q

What are the sources of
ammonia for Urea synthesis in
the liver

A

Glutamine and Glutamate (glutamate synthesized from alanine

and aKG)

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14
Q

What is the essential activator of

the urea cycle?

A

NAG. N acetyl glutamate.

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15
Q

What enzyme does the activator

of urea synthesis activate?

A

CPSI Carbamoyl phosphate synthetase I

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16
Q

What are the first two substrates

for the urea cycle?

A

Carbamoyl phosphate and L-Ornithine

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17
Q

Where does CPSI catalyze its

reaction and what is its product

A

In the mitochondria Carbamoyl phosphate

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18
Q

Where does the Urea cycle take

place?

A

L-Citrulline synthesis occurs in the mitochondria, by Ornithine
transcarbamoylase, and the rest occurs in the cytosol.

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19
Q

What amino acid activates the

enzyme NAGS

A

Arginine, indicating that the urea cycle is highly saturated.

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20
Q

What protein connects the urea

cycle and citrate cycle?

A

Aspartate Oxaloacetate converted via asp1artate transaminase

cofactor: alpha-KG Glutamate

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21
Q

What happens to most of the
ammonia absorbed by the portal
vein?

A

80% is immediately converted to Urea for elmination in urine.
This includes free ammonia as well as glutamine and alanine.

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22
Q

How does ammonia excretion

change during acidosis?

A

It increases, becuase there is increased activity of the
Proton/Potassium ATPase pump. The tubular fluid is more
acidic, there is more protonation of NH3 to NH4, trapping
ammonium in the urine and increasing excretion.

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23
Q

From what amino acid do renal
tubular cells obtain NH3 for
excretion?

A

Glutamine1 or glutamate.

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24
Q

How does the ammonia
concentration of portal blood
compare to systemic blood?

A

5-10 times higher, highest during the postprandial period.
Ammonia is absorbed from food and from the breakdown of
urea by intestinal flora even in a starved state.

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25
Q

How does resting muscle affect
ammonia levels? Active
muscle?

A

Resting muscle absorbs low levels of amonia and secretes
Glutamine Active muscle generates and secretes lots of
ammonia and alanine

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26
Q

How do Kidneys affect

ammonia balance

A

They create more ammonia than they can secrete,

and it is up to the liver to generate urea for elimination.

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27
Q

How does hyperammonemia

affect the brain

A

Brain
takes up some ammonia, and produces/secretes Glutamine.
Excessive ammonia in the blood will increase brain uptake and
generate cerebral edema. Glutamine is taken up by astrocytes Increases the synthesis of
both Glutamate GABA Chronic/acutely this will cause chronic
elevations in both glutamatergic and gabaergic signaling.
Causes edema of astroglia cells. Lethargy Confusion/strange
behavior Hypotonia Coma Seizures

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28
Q

What are the causes of neonatal

hyperammonemia?

A

Defective enzymes in the urea cycle

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29
Q

What is the most common
enzyme deficiency causing
neonatal hyperammonemia?

A

1) OTC, Ornithine transcarbamylase defect Very High

Orotate/Orotic acid in urine Is DOMINANT mutation, all the
rest are recessive. Blood: High glutamine, high alanine

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30
Q

Second most common ezyme
def causing neonatal
hyperammonemia?

A

ASL, Arginosuccinate lyase defeciency High Arginosuccinate,

High citrate Low Arginine, low Ornithine High Orotic acid.

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31
Q

Third most common ezyme def
causing neonatal
hyperammonemia?

A

ASS, Arginossucinate Sythnetase deficiency Citrulinemia very

high citruline, high orotic acid low arginine

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32
Q

What does pyruvate carboxylase deficiency cause?

A

Hypoglycemia, Hyperammonemia, Lactic acidosis, Low
glutamate, Low aspartate, impaired myelination. Inhibits
production of oxaloacetate, decreasing availability of Citric
Acid Cycle substrates. Decreased TCA cycle activity causes
pyruvate to be shunted towards lactic acid production (like its
hypoxia does) causing lactic acidosis. It also inhibits
gluconeogenesis. Pyruvate carboxylase is the first enzyme in gluconeogenesis converting pyrvate to oxaloacetate. Causes
hypoglycemia that affects the brain most severely Causes low
aspartic acid levels, Aspartate is synthesized from oxaloacetate,
Aspartate is essential for urea cycle, so there is
hyperammonemia too. Aspartate is a precursor for Glutamate,
low brain glutamate levels. Aspartate is a precursor for myelin,
there is low myelination.

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33
Q

What is the most common cause

of hyperammonemia in adults?

A

Hepatic encephalopathy. Liver failure, impaired urea cycle.
Acute: Brain edema and rapid impairment/death
Acetominophen toxicity, Hepatitis B Chronic alcoholism,
progressive cognitive failures, and mental decline Hepatitis C

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34
Q

What are the 3 vital functions

lost during acute liver failure?

A

1) ammonia detoxification -> hyperammonemia, brain edema
2) gluconeogenesis -> hypoglycemia hypoglycemia induces
hypoinsulinemia. 3) Lactate clearance -> lactic acidosis The
first step in liver gluconeogenesis, lactate -> pyruvate ->
oxaloacetate -> PEP

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35
Q

How is brain edema treated?

A

Mannitol. lots of osmotic diuresis

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36
Q

Potential drug targets of hepatic

encephalopathy

A

anti-inflammatory drugs p38 inhibitors, both to inhibit

microglial activation GABA receptor inhibitors

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37
Q

Other ways to prevent
hyperammonemia or prevent
ammonia absorption

A

low protein diet antibiotics to decrease intestinal bacteria alpha
keto acid derivatives of branched chain amino acids consume
lactulose, which will acidify gut lumen, convert NH3 to NH4
and decrease ammonia absorption. hemodialysis

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38
Q

Where do the two nitrogens in

urea come from?

A

One from free ammonia and one from aspartate

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39
Q

How do urea cycle defects cause

orotic acidemia?

A

Carbamoyl phosphate is a pyrimidine synthesis precursor, thus
excess pyrimidines and degradation products

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40
Q

What is a free radical?

A

A molecule with an unpaired valence electron

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41
Q

What is the oxygen paradox

A

Anaerobic organisms evolved first, and oxygen is inherently
dangerous to them because of free radical generation, and
anaerobic organisms typically don’t have antioxidant systems.

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42
Q

What is an oxidant What is a

reductant

A

Oxidant: something that oxidizes another chemical by: taking
electrons, taking hydrogen, or adding oxygven Reductant:
Adds electrons, adds hydrogen, or removes oxygen.

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43
Q

half life of hydrogen peroxide

half life of hydroxyl radicals

A

H2O2, a few minutes hydroxyl radical, nanoseconds

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44
Q

What are ROS?

A

ROS are atoms or molecules formed by the incomplete
reduction of oxygen. Radical ROS: Superoxide O2- Hydroxyl
radical OH- Hydroperoxyl HO2- Non-radical ROS: Hydrogen
peroxide H2O2 Singlet oxygen 1O2 Ozone O3

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45
Q

What are Reactive Nitrogen

Species

A

Radical RNS: Nitric Oxide NO Nitrogen Dioxide NO2- Nonradical:
Peroxynitrite ONOO

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46
Q

What
are the steps in the
complete oxidation of oxygen

A

O2 O2- superoxide anion H2O2 hydrogen peroxide OHhydroxyl

radical H2O water

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47
Q

What is the most biologically

reactive ROS?

A

Hydroxyl radicals.

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48
Q

What are the good and bad roles

of ROS?

A

bad: increased ROS load causes apoptosis Damage
DNA/proteins/Lipids in the cell good: essential for microbial
defense Platelets use ROS as signaling to recruit more platelets
and promote coagulation.

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49
Q

What enzymes remove ROS

A

Superoxide dysmutase Catalse guaiacol peroxidase (GPX)

Glutathione, not an enzyme tho

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50
Q

Diseases that ROS are involved

in pathogenesis

A

Alzhemiers, Parkinsons, Schizophernia Cancer Cataracts
Hypertension, Atherosclerosis, Ischemia Asthma Chronic
inflammatory disorders: Lupus, Multiple sclerosis Rheumatoid
arthritis

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51
Q

Exogenous sources of radicals

A

Ionizing or UV radiation Pollutants Cigarette smoke Drugs and
xenobiotics

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52
Q

How does UV radiation generate

free radicals?

A

from hydrogen peroxide. Splits it into two hydroxyl radicals

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53
Q

How does gamma radiation

generate ROS?

A

Can generate hydroxyl radicals from water.

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54
Q

Enzymes that generate ROS

endogenously

A

Lipoxygenase Xanthine oxidase Cyclooxygenase Cytochrom
p450 Monooxygenase NO synthase NADPH oxidase
Byproduct of the Electron transport chain and partial oxygen
reduction

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55
Q

What is the common component

of Cytpchrome p450 enzymes.

A

Heme is a cofactor

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56
Q

What enzyme generates ROS in
the ER after alcohol
consumption

A

CYP2E1 a mixed function oxidase (not alcohol
dehydrogenase) It is IN THE ER Converts ethanol to
acetaldehyde (Reducing it), and uses NADPH and O2 as
cofactors, generating NADP+ and H2O, or can generate
reactive oxygen species.

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57
Q

What reaction does Xanthine

oxidase catalyze?

A

hypoxanthine, O2, and H20 -> H2O2 and xanthine xanthine

O2 and H20 –> uric acid and H2O2.

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58
Q

What precursor does NOS use to

synthesize NO?

A

L-Arginine

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59
Q

What is the main enzyme
neutrophils use to generate
ROS?

A

NADPH oxidase. Generates superoxide anions O2- Adds a

single electron to O2.

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60
Q

What is the organelle whose
main function is generating ROS
and RNS? What are a few
examples of eznymes in it?

A

Peroxisomes NO synthase Xanthine oxidase Urate oxidase

Acyl-CoA oxidase D-amino acid oxidase

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61
Q

What is the main enzyme
neutrophils use to generate
RNS? What other products can it
generate?

A

Myeloperoxidase. MPO uses H2O2 and NO2 (nitrite) to
generate RNS intermediates It can also generate several very
strong acids: H2O2 and Cl, Br, SCN, hypochlorous HOCl
hypobromous HOBr hypothiocyanous acids HOSCN Or it can
generate Tyrosyl radicals from H2O2 and Tyrosine.

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62
Q

List 5 endogenous anti-oxidants

A

Glutathione (replenished by gluathione reductase) Catalse
Superoxide Dismutase CoEnzyme Q-10 Cytochrome C
Peroxidase

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63
Q

List some dietary anti-oxidants.

A

ACE vitamins, vitamins A, C, E Alpha lipoic acid N-acetyl
cystine Polyphenols Green tea and Olive oil Proanthocyanidins
Red wine Blueberrys Chocolate Ginsengs.

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64
Q

FrontBack Newborn screens for inborn
errors of Amino acid
metabolism (6)

A

Tyrosinemia Arginosuccinic Aciduria Citrullinemia

Phenylketonuria Maple Syrup Urine disease Homocystinuria

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65
Q

Newborn screens for inborn
errors of Organic Acid
metabolism

A

Propionic acidemia Glutaric acidemia type 1 Isovaleric acidemia
Methylmalonic aciduria Mathylmalonyl-coA mutase deficiency

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66
Q

Newborn screens for inborn
errors of fatty acid
metabolism

A

Long chain hydroxyacyl-CoA dehydrogenase deficiency Medium
chain acyl-CoA dehydrogenase deficiency Very long chain acyl
coa dehydrogenase deficiency Trifunctional protein deficiency
Carnitine uptake defect

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67
Q

Newborn screens for inborn
errors of other miscelaneous
systems

A

Cystic fibrosis Congenital hypothyroidism Biotinidase deficiency
Congenital adrenal hyperplasia Galactosemia SCID

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68
Q

What enzyme defect causes

alkaptonuria?

A

HGD, homogentisate dioxygenase.

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69
Q

What amino acid degradation
pathways are impaired in
alkaptonuria?

A

Homogentisate is downstream of both Tyrosine and Phenylalanine
metablism, when it accumulates it is excreted in urine in its
oxidized form, Alcaptone.

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70
Q

Symptoms of alkaptonuria?

A

Ochronosis. Black pigment deposition of homogentisate in the
connective tissue. Dense black pigment in the intervertebral discs,
synovial cartilage, tendons and ligaments, ear and nose cartilage,
skin. Dark/black urine especially after protein rich meal. Joint and
bone pain develops after age 30 and can be debilitating. Bone
density can be low, fractures. Tendons and ligament tears also
increase. Galstones, Kidney stones increased rate. Valvular heart
disease at increased rates.

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71
Q

What is the most frequent

inborn metabolic disease?

A

Phenylketonuria

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72
Q

What is the Guthrie assay?

A

A drop of blood is obtained from an infant and collected on a
piece of filter paper. A disk is punched out and placed on an agar
gel plate containing Bacillus subtilis and B-2-thienylalanine. The
agar gel is able to support bacterial growth but the B-2-
thienylalanine inhibits bacterial growth. However, in the presence
of extra phenylalanine leached from the impregnated filter paper
disk, the inhibition is overcome and the bacteria grow.

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73
Q

What are the two types of

Phenylketonuria?

A

Classical PKU - Phenylalanine hydroxylase defect Cofactor

deficient PKU - Dihydrobiopterin reductase defect.

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74
Q

Symptoms of PKU

A

Mental retardation, correlates strongly with the load of
phenylalanine in blood during infancy Seizures Hypertonic
muscles Musty urine and sweat Fair hair and skin High plasma
phenylalanine

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75
Q

How is phenylalanine

metabolized in PKU

A

aminotransferase generates phenylpyruvate and alanine
Phenylpyruvate converted to Phenylacetate and Phenyllactate
which makes urine smell.

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76
Q

What transports

phenylalanine into neurons?

A

LAT1 the neutral amino acid transporter

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77
Q

How does extremely high
phenylalaline levels affect
neurons?

A

Causes abnormal myelination Abnormal protein synthesis and

neurotransmitter production.

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78
Q

Phenylketnouria treatment

A 
Very strict control of phenylalanine intake Tyrosine and
Tryptophan supplementation (Phenylalanine is a precursor)
Phenylalanine ammonia lyase enzyme substitution therapy.
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79
Q

Essential amino acids

A

PVT TIM HALL

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80
Q

What is missing in cofactor

deficient PKU?

A

Dihydropteridin Reductase (DHPR) usually, Therefore
Tetrahydrobiopterin cannot be regenrated from Dihydrobiopterin.
or A defect in de novo synthesis of biopterin (synthesized from
from GTP)

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81
Q

How is cofactor deficient

PKU diagnosed?

A

Administering THB, tetrahydrobiopterin decreases plasma

Phenylalanine levels and increases Tyrosine levels

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82
Q

How is cofactor deficient

PKU treated?

A

strict control of phenylalanine in diet. L-DOPA 5-OH-tryptophan,
and tetrahydrobiopeterin supplementation.

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83
Q

What enzyme is defective in

Albinism?

A

Tyrosinase. preventing Melanin synthesis from tyrosine

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84
Q

What are the symptoms of

albinism

A

Light sensitivity Vision defects Skin cancer

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85
Q

What causes Maple Syrup

Urine Disease?

A

Branched Chain Ketoacid Dehydrogenase defect. BCKD

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86
Q

What amino acids are
involved in maple syrup urine
disease?

A

Leucine Isoleucine Valine

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87
Q

What subunits are involved in
oxidative decarboxylation by
BCKD, what are the
cofactors for each

A

E1 Ketoacyl dehydrogenase TPP, thiamine pyrophosphate E2
Dihydrolipoyl transacetylase FAD E3 Dihydrolipoyl
dehydrogenase NAD

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88
Q

What subunit of the BCKD
enzyme is common to other
enzymes and what are they?

A

E3 BCKD Pyruvate dehydrogenase alpha ketoglutarate

dehydrogenase.

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89
Q

Symptoms of BCKD

deficiency

A

Growth retardation Ketoacidosis Brain edema Seizures Maple
Syrup urine Increased Branched chain amino acids and keto acids
in plasma Leucine and ketoisocaproic acid especially.

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90
Q

How does leucine cause brain

toxicity?

A

Edema Impaired myelination Impaired protein and

neurotransmitter synthesis

91
Q

What transporter brings

leucine into neurons

A

LAT1 . Neutral amino acid transporter

92
Q

How is ketoisocaproic acid

toxic to the brain?

A

ketoisocaproic acid + glutamate makes leucine + alphaketoglutarate
It reduces glutamate and GABA availability. Causes
a defect in transport of reducing equivalents

93
Q

What transporter brings
ketoisocaproic acid into
neurons?

A

MCT1 monocarboxilate transporter.

94
Q

What is the GABA shunt?

A

a-KG from the TCA cycle shunted to produce succinate and
NADH via a GABA intermediate. a-Ketoglutarate –> glutamate –
> GABA –> GABAT –> Succinic semialdehyde –> succinate.

95
Q

What reducing equivalents
are transported in/out of the
mictochondrial membrane?

A

Malate/aKG Aspartate/Glutamate. Malate aspartate shuttle

96
Q

Where is the defect in
thiamine responsive MSUD Therapy for BCKD
defeciency?

A

In the E 1 subunit of the BCKD, which uses TPP as a cofactor. Diet control of Leu Ile Val. Hemodialysis during crises Liver
transplant.

97
Q

What happens if there is a

defect in the E3 subunit

A

Pyruvate dehydrogenase aKG dehydrogenase BCKD are all

deficient Lactic acidosis and severe ketoacidosis.

98
Q

What two enzymes metabolize

alcohol?

A

Alcohol dehydrogenase and aldehyde dehydrogenase Or

CYP2E1

99
Q

Where is CYP2E1 enzyme

located?

A

In the ER

100
Q

Where is alcohol dehydrogenase

located?

A

Cytosol

101
Q

Where is aldehyde

dehydrogenase located?

A

Mitochondria

102
Q

Which of the enzymes in alcohol

metabolism are inducible?

A

CYP2E1 is highly inducible by ethanol

103
Q

Which ezyme in alcohol
metabolism is high affinity?
which is low affinity?

A

Alcohol dehydrogenase is high affinity and non-inducible

CYP2E1 is low affinity and highly inducible

104
Q

What is ethanol generated from

in yeast fermentation?

A

Pyruvate –> Acetaldehyde –> Ethanol It allows they to
survive anaerobic conditions, and provides ethanol as a weak
antimicrobial.

105
Q

How is alcohol metabolized
differently in men and women
and in a fed or fasted state

A

Women eleminate alcohol at about 2/3 the rate of men Fasted
state is also about 2/3 the rate of elemination in a fed state.
High fat and high protein meals make it elmiinate the fastest.

106
Q

What is responsible for the toxic
effects of alcohol metabolised by
alcohol dehydrogenase?

A

acetaldehyde buildup

107
Q

What are the toxins built up
when alcohol is metabolized by
CYP2E1

A

Reactive oxygen species, as well as acetaldehyde.

108
Q

How does ethanol increase

CYP2E1 levels.

A

It induces its expression and also prolongs its half life, by
inhibiting ubiquitination of CYP2E1

109
Q

How does alcohol dehydrogenase

affect the redox balance?

A

Ethanol metabolism by alcohol dehydrogenase produces
NADH. Produces high NADH/NAD+ levels most specifically
IN THE LIVER. decreased beta oxidation and FA degradation
decreased citrate cycle, Acetyl-CoA accumulation, Increased
FA synthesis increased Glycerol 3 phosphate, Increased FA
synthesis TCA cycle inhibited, but need to regenerate NAD+,
so LDH is activated and Lactic acidosis occures.
Gluconeogenesis is inhibited, hypoblycemia.

110
Q

How does CYP2E1 ethanol
metabolism affect the redox
balance?

A

CYP2E1 doesn’t use NAD/NADH It uses O2 as the electron
acceptor instead of NAD+, and Consumes NADPH + H and
O2, to generate two H2O. It is by this process that it can
generate ROS during incomplete oxidation.

111
Q

How is acetaldehyde toxic?

A

Mainly by Adduct formation, with virtually any kind of
molecule in the cell. DNA, and DNA repair enzymes -> DNA
mutations GSH and antioxidant enzymes, -> more oxidative
damage and DNA mutations Apolipoproteins –> decreased VLDL production Tubulin –> Decreased VLDL secretions
These changes are the major causes of cancer and fatty liver.

112
Q

How does alcohol negatively

affect the GI tract?

A

It can increase intestinal permeability and Inhibit
Reticuloendothelial cell system activity, Increasing infections
and sepsis.

113
Q

How does low does vs. chronic
or medium/high does alcohol
affect the cardiovascular system?

A

Low dose Increases HDL levels, Decreases oxidized LDL
levels. Reduces platelet aggregation Increases fibrinolysis
Reduces stress medium or high dose Increases risk of:
Hypertension Ischemic heart disease Coronary heart disease
Ischemic or hemorrhagic stroke.

114
Q

What are possible consequences

of strong CYP2E1 induction?

A

hypoxia (uses O2 as the e acceptor) oxidative stress, ROS
generation acetaldehyde accumulation accumulation of drug
intermediates and altered drug metabolism. carcinogenesis
over long periods alteration in testosterone metabolism

115
Q

What random intracellular
signaling pathways does chronic
alcoholism affect?

A

Oxidative stress increases JNK and c-Fos, c-Jun signaling.
Increases Cyclin D1, pro-mitotic in hepatocytes CYP
induction decreases Retinoic acid, decreasing RAR/RXR
levels, decreasing apoptotic signals. Overall, increased
cyclinD1 and decreases apoptosis, carcinogenic.

116
Q

What major drug does CYP2E1

metabolize?

A

PARACETAMOL aka Acetaminophen.

117
Q

How is acetaminophen
metabolism different in normal
vs. alcoholics?

A

Paracetamol/acetominophen is normally metabolized without
toxic intermediates. In an alcoholic condition, CYP2E1 is
induced highly, and metabolism of paracetamol by CYP2E1
produces the highly toxic NAPQI. N acetyl p
benzoquinonimine, NAPQI. Its downstream metabolites also
generate other ROS. So an alcoholic who takes
acetominophen at a time when they have not consumed any
alcohol will have it almost all converted by this toxic
intermediate generating pathway and are at risk for acute liver
toxicity.

118
Q

What kind of receptor is the

Insulin receptor?

A

A tyrosine kinase receptor, it directly phosphorylates its

insulin receptor substrates, IRSs.

119
Q

What pathways does the Insulin

receptor activate?

A

via SH2 domains, it binds GRB2 which couples it to the
Ras/MAPK growth factor pathway, and PI3K which activates
most of its metabolic effects. PI3K activates AKT, also called
Protein kinase B, Inhibits GSK3, which disinhibits glycogen
synthase, and glycogen synthesis increases. activates FOxO
transcription factors, inhibiting gluconeogenesis activates
mTOR signaling, increasing protein synthesis. activates
SREBP (sterol regulator element binding proteins)
transcription factors, increasing lipid synthesis. GRB2,
activates SOS, a

120
Q

What are the major pathways that
inhibit insulin receptor
substrates?

A

JNK : c-jun N terminal kinases and IKKbeta : I-kappa-B
kinase beta. Both are serine kinases that phosphoinhibit IRS at
serine residues, while the activating insulin receptor
phosphorylates tyrosines. SOCS3, Suppressor of cytokine
signaling, binds and inhibits the insulin receptor on its
cytosolic side. All of these pathways are induced by IL-6 and
TNFalpha.

121
Q

What are the two major insulin

sensitising adipokines?

A

Leptin and adiponectin

122
Q

What are the effects of leptin in

the liver

A

Stimulates gluconeogenesis by activating PEPCK Increases
glycogen consumption. Increases beta oxidation by activating
PPAR alpha inhibits lipogenesis, and inhibits expression of
SREBPs

123
Q

Leptins actions in muscle

A

Stimulates AMPK Stimulates fatty acid oxidation. via

PPARalpha activation.

124
Q

What doe levels of leptin

correlate best with.

A

The amount of adipose tissue in a person. Obese people have
higher leptin levels, and also can develop leptin resistance
much like insulin resistance. Leptin does not increase during
acute overfeeding. Leptin levels drop during starvation.

125
Q

Where is adiponectin
synthesized? What are its main
targets?

A

Adipose tissue. Its receptors are in the liver and muscles. Its
essential function is to enhance liver and muscle responses to
insulin.

126
Q

What are the effects of

adiponectin on skeletal muscle

A

The activation (tyrosine phosphorylation of) the insulin
receptor is enhances. Enhances FA oxidation Increases
glucose uptake Increases lactate production Phosphoinhibits
acetyl-CoA carboxylase (inhibiting FA syntehsis)

127
Q

Effects of adiponectin on liver

A

Inhibits FFA uptake and VLDL production. Increases FA
oxidation Increases aerobic glucose utilization Increases
glycogen synthesis Inhibits gluconeogenesis.

128
Q

What are the major inhibitors of

the adipokines?

A

Inflammatory cytokines TNFalpha and IL-6 Their levels are
increased in obesity, and they decreases the level of
adiponectin specifically. Levels of TNF-alpha are correlated
with BMI increases.

129
Q

What signaling pathways do
inflammatory cytokines activate
that can cause insulin resistance?

A

JNK and IKKbeta serine kinase pathways.

130
Q

What are major factors in insulin

resistance?

A

TNFalpha, IL-6 proinflammatory signaling. ER stress of beta
cells, inhibiting insulin synthesis. ER stress in adipocytes,
decreasing adiponectin synthesis. TKR2 and TLR4 expression
are also increased on adipocytes in obesity, and can be
activated at low levels by saturated fatty acids, causing a loop
or pro-inflammatory signaling. The Unfolded Protein
Response, also induces pro-inflammatory signaling, insulin
resistance.

131
Q

What transcription factor is the
major regulator of adipocyte
differentiation/function

A

PPARgamma. and its receptor RXR, retinoid X receptor.

132
Q

How is BMI calculated

A

Kg body weight / height in meters squared

133
Q

Normal BMI?

A

18.5-25 kg/m2

134
Q

Overweight BMI

A

25-29.9 kg/m2

135
Q

Obese BMI’s mild, moderate,

severe

A

30-35 kg/m2 35-40 Above 40

136
Q

What is the threshold for

abdominal obesity?

A

men above 94 centimeters women above 80 centimeters.

137
Q

What is the percentage of obesity

in the US? In Europe?

A

above 25% in the US about 20% in europe.

138
Q

Which glucose transporter is

insulin sensitive?

A

GLUT4

139
Q

Which glucose transporter is
expressed on beta cells? Where
else is it expressed?

A

GLUT-2 Hepatocytes Kidney Enterocytes It is low affinity

140
Q

Which glucose transporter(s) is
involved in basal glucose uptake
and is not insulin sensitive?
Where is it express

A

GLUT-1 expressed throughout body, is saturated at normal
glucose levels for continual glucose uptake. In brain, RBCs,
encothelial cells, many body tissues. GLUT-3 high affinity,
neurons and other neural cells specifically.

141
Q

Basic differences between
Hormone sensitive lipase and
Lipoprotein Lipase

A

Hormone sensitive lipase breaks down triglyceride into fatty
acid and glycerol during fasting under influence of increased
epinephrine/cortisol or decreased insulin. Lipoprotein lipase
breaks down chylomicron/VLDL and is involved in uptake of
triglyceride into adipose tissues It needs Apo-CII cofactor.

142
Q

How does insulin affect HSL

How does glucagon affect HSL

A

Insulin causes phosphoprotein phosphatase to
dephosphorylate and inactivate HSL. Glucagon causes PKA to
activate HSL by phosphorylation.

143
Q

What reaction does HSL

catalyze?

A

It converts TAGs to DAGs and DAGs to MAGs. It cannot

remove the final FA from a MAG. That requires MAG lipase.

144
Q

What other lipases can degrade

TAGS besides HSL?

A

TAG lipase found in lysosomes, in liver and adipose. Esterase,
High affinity to short chain fatty acids.

145
Q

High yield facts about leptin and

ghrelin.

A

from Adipose tissue, and it induces satiety through its action
on the hypothalamic ARCUATE nucleus, exerting its effect
through 2 main actions : 1) Decreases Neuropeptide Y (NPY)
and Agoutin-Related Peptide(AgRP) ( an appetite stimulant )
2) Increases ProOpioMelanoCortin( POMP) and Cocaine
Amphetamine Regulated Transcript (CART) ( Appetite
suppressants) - Ghrelin is secreted from the stomach
FUNDUS and the pancreatic Epsilon cells. It is the hunger
hormone, and it counteracts Leptin’s actions. - Obese patient
usually has high Leptin levels due to high adipose tissue –>
leads to Leptin desensitization –> Loss of Leptin action (
much like DM2 ) - Sleep deprivation increases Ghrelin and
decreases Leptin.

146
Q

How does leptin affect appetite?

A

Decreases appetite, induces satiety. In the hypothalamic
arcuate nucleus: Decreasing Neuropeptide Y (NPY)
Decreasing Agoutin-Related Peptide(AgRP) Increasing
POMC Increasing Cocain amphetamine regulated transcript
(CART) Increases CRH, TRH

147
Q

How does leptin affect

carbohydrate metabolism

A

decreases insulin secretion Increases liver gluconeogenesis
activates Glucose 6 phosphatase Activates PEPCK Increases
muscle GLUT4 expression.

148
Q

How does leptin affect lipid

metabolism

A

increases beta oxidation, by inducing carnitine
palmitoyltransferase, increasing FA transport into the
mitochondria Decreases lipid synthesis, by lowering
expression of SREBP.

149
Q

How does leptin affect body

temperature?

A

It increases temperature, by increasing UCP2 expression,

uncoupler.

150
Q

How does leptin inhibit insulin

signal transduction?

A

Activates JAK2, then STAT3, then SOCS. the Suppressor of
Cytokine Signalling. It can bind and inhibit the activity of
BOTH the Insulin Receptor and/or the Leptin receptor It is
induced by IL-6 and TNF-alpha as well.

151
Q

What enzymes of fatty acid
metabolism are affected by
insulin?

A

Insulin activates Acetyl-CoA Carboxylase ACC. First step in
cytosolic FA synthesis. Increases glucose uptake GLUT4
activity Insulin increases PFK-2 activity (by
dephosphorylating it with, which generates Fructose 2,6
bisphosphate F26BP, which potently activates PFK-1, the
committed, rate limiting step of glycolysis. F26BP also
inhibits Fructose 1,6 bisphosphatase, inhibiting
gluconeogenesis.

152
Q

What is are some genetic cause

of obesity

A

MC4R mutations are the most frequent genetic cause of
obesity. Melanocortin receptor which is found to also have a
strong role in satiety. Responsible for some of the satiating
effercts of POMC and the stress response. Null mutations of
Leptin or the Leptin Receptor.

153
Q

Effect of AgRP

A

Agouti-related peptide. An inverse agonist (inhibitor/silencer)
of MC3R and MC4Rs. Causes increased food intake

154
Q

Effect of NPY

A

Synthesized by arcuate nucleus acts on paraventricular
nucleus and ventromedial nucleus to increase food intake
Weight loss increases NPY

155
Q

Effect of Tyrosine-Tyrosine

Protein (PYY)

A

decreases intestinal motility, emptying of stomach, decreases
appetite PYY defects can cause obesity

156
Q

What is metabolic syndrome

A

having at least 3 of these 5 symptoms Hypertension
>130mmHg High blood TAGs High fasting glucose Above
5.6mmol/L Low HDL Central obesity above 102cm males
above 88cm females.

157
Q

What are the consequences of

obesity for this exam?

A

Metabolic syndrome T2DM, insulin resistance Non-alcoholic
fatty liver Ischemic heart disease Stroke Hyperuricemia, Gout
Breast cancer, Endometrial cancer Colorectal cancer
Polycystic ovarian syndrome Sleep apnea Asthma Depressed
respiration, lung infections Depression Fatigue Vertebral
compression, Hernia

158
Q

Obesity therapy

A

lifestyle change. lose 5-10% of current body mass over 6
months. Goal is for heart to be at aerobic range, 220bpm
minus the age. 150 minutes of exercise a week, walking or
running. no more than 2 consecutive days off. Psychiatric
support to gain motivation. Medicine only recommended if
BMI is above 30, or if it is above 27 and there is notable
comorbidities. Orlistat, inhibits intestinal lipases, preventing
absorption of intestinal fats. Surgical gastrectomy, only with
severe comorbidity if BMI is above 35 kg/m2

159
Q

ellular mechanisms of beta cell

insulin release

A

two main pathways: 1) High glucose, influx through
GLUT2 transporter Increased ATP/ADP ratio ATP CLOSES
the ATP sensitive K+ channel. CLOSING of this channel
keeps K+ in preventing it from hyperpolarizing the cell.
CLOSING of this channel causes DEPOLARIZATION of the cell. Activates the Voltage dependent calcium channel.
Insulin secretory granule release, activation of Ca++
sensitive TF pathways to induce insulin production. 2)
Incretin proteins GLP-1 or GIP bind their receptors,
increasing cAMP levels, activating PKA. PKA
phosphorylates proteins involved in the secretory process,
potentiating Ca++ induced insulin release.

160
Q

What pathways regulate insulin
release in independently of the
ATP-dependent K channel?

A

cAMP levels and PKA, regulated by the incretins, glucagon,
adrenalin, somatostatin, the neurotransmitter PACAP. PKC,
regulated by Acetylcholine Free Fatty acids acting through
GPR40.

161
Q

Insulin effects in skeletal muscle

A

GLUT4 translocation, increased glucose uptake Activates

glycogen synthase

162
Q

Insulin effects in Adipocytes

A

SREBP activation, increased lipid synthesis PKA activation,

inhibited lipolysis, no lipid releas

163
Q

Insulin effects in Hepatocytes

A

Akt decreased gluconeogenesis, increased glycogen
synthesis SREBP activation, increased lipid synthesis
mTOR activation, increased protein synthesis.

164
Q

Consequence of insulin deficiency

A

Ketoacidosis Hyperglycemia -fatigue, -seizures -coma
Osmotic diuresis, polyuria and polydipsia Increased
lipolysis and decreased cell growth, loss of body weight

165
Q

Why is insulin resistance and total

insulin deficiency differ?

A

Insulin resistance does not equally inhibity all of insulin

signalling pathways.

166
Q

What pathways are affected most
and affected least in insulin
resistance?

A

SREBP signaling is retained The effects of insulin on
carbohydrate metabolism are mostly lost, while its affects
increasing the syntehsis of fatty acids and triglycerides in
the liver and adipose are retained.

167
Q

What kinds of extracellular signals
can activate intracellular serine
kinases that inhibit IRS signaling?

A

Fatty acids Cytokines Leptin

168
Q

Insulin effect on Beta-cells?

A

Enhances glucose sensitivity Ras/MAPK signaling,
trophic/mitotic factor Akt signaling inhibits apoptosis These
effects are part of the reason why T2DM can progress to
T1DM, since insulin resistance inhibits these trophic
signals, causing beta cell apoptosis.

169
Q

What causes inflammation of
adipose, hypertrophy or
hyperplasia?

A

Hypertrophic growth, swelling of individual cells. This is
the kind that causes inflammation and is the kind stimulated
by excessive eating. Causes a degree of adipocyte apoptosis
and increases macrophage infiltration of the tissue,
increasing inflammation.

170
Q

What are the signals induced by

TNFalpha and IL-6, IL1beta

A

IKKbeta, JNK SOCS all inhibitory to IRS signaling NFkappaB

AP-1 Pro-inflammatory signals.

171
Q

What happens when insulin

signaling is lost from adipocytes

A

There is increased lipolysis and FFA release. Decreased

glucose uptake. Decreased Adiponectin Increased Leptin

172
Q

How are free fatty acids toxic to

cells? essential card

A

weakly activate cytokine receptors Activate FAT/CD36
membrane receptor Cause ER stress -> activate unfolded
protein response -> activates JNK, also activate TLRs,
inducing pro-inflammatory signaling.
Genetic predisposition This is exacerbated by obesity,

173
Q

What is the most important factor

for development of type 2 diabetes

A

inflammation, and FFA induced insulin resistance. But type
2 diabetes and insulin can develop on its own in non-obese
people.

174
Q

How is visceral/central/abdominal
adipose different from
subcutaneous adipose?

A

Visceral adipose: Higher cytokine secretion More
macrophage infiltration which are also more inflammatory
Converts cortisone into glucocorticoid cortisol Hormone
and cytokin outflow from abdominal fat hits the liver first
via portal blood flow, contributing to hepatic insulin
resistance much more than subcutanoues fat.

175
Q

Metabolic syndrome 5

characteristics

A

Central obesity Hypertension High TAG level Low HDL
High fasting glucose above 5.6 (indicates insulin resistance)
It is like Cushings syndrome but without elevated cortisol
(not as high).

176
Q

What are the pre-receptor
conversions of glucocorticoids in
Liver Muscle Adipose

A

11-beta-Hydroxysteroid Dehydrogenase 1 11B-HSD1

Converts cortisone to cortisol, activating it

177
Q

What are the pre-receptor
conversions of glucocorticoids in
Kidneys and Intestines

A

11-beta-Hydroxysteroid Dehydrogenase TWO 11B-HSD2

Converts cortisol to cortisone, inactivating it.

178
Q

How does 11b-HSD1 knockout

affect mice

A

protective against obesity and insulin resistance even in
overfeeding. indicates that cortisol signaling in the liver,
adipose, and muscle is a key component to developing
metabolic syndrome and insulin resistance.

179
Q

How does 11b-HSD1

overexpression affect mice

A

generates metabolic syndrome if expressed just in the liver,

then metabolic syndrome without obesity.

180
Q

What drugs induce insulin secretion

A

“insulin secretagogues” Sulfonylurea drugs bind to the ATPsensitive
K+ channel (Katp channel) and keep it shut
irrespective of ATP levels. Causing cell depolarization and
secretion NSIS, Non-sulfonylurea types, also bind the Katp
channel, but at a different site than the sulfonylureas. GLP-1
receptor agonists, DPP4 inhibitors, (DPP4 degrates incretins
GLP-1 and GIP, so DPP4 inhibitors increase incretins)

181
Q

What are the anti-diabetic drugs?

A

PPAR-gamma agonists, Metformin, Sodium glucose cotransporter
inhibitors (SGLT2 inhibitors).
Thiazolidinediones, PPAR-gamma agonists. These make
cells more sensitive to insulin, Decrease lipolysis, decrease
serum FFAs, Decrease TNF-alpha levels Decrease Leptin
levels Increase Adiponectin. Biguanides: Only one, its
Metformin Metformin activates AMPK, which overal
lowers hepatic lipids, and inhibits PKC, which is part of
insulin resistance Decreases liver gluconeogenesis
Decreases SREPB1 expression Decreases ACC activity
Decreases Fatty acid synthesis Decreases VLDL synthesis
Increases fatty acid oxidation Increases liver insulin
sensitivity. Increases glucose uptake by muscle

182
Q

Anti-diabetic drug list

A

GLP-1 receptor agonists DPP-4 protease inhibitors Alpha
glucosidase inhibitors Insulin secretagogues Sulfonylurea
Non-sulfonylurea insulin secretagoges SGLT2 inhibitors
Biguanides, Metformin Thiazolidinediones, PPAR gamma
agonists. Insulin!

183
Q

Things that can cause
vascular damage leading to
atherosclerosis

A

High cholseterol Turbulent blood flow Shearing forces sdLDL
oxLDL Chronic Inflammation, possibly some viruses, C.
pneumonia

184
Q

Cholesterol uptake

transporters in the intestine

A

proximal jejunum NPC1 NPC1L1

185
Q

ER transporter of cholesterol

A

ACAT forms cholesterol esters from cholesterol acyl coa

cholesterol transport protein

186
Q

What transcription factor
regulates liver synthesis and
export of cholesterol?

A

LXR Liver X Receptor

187
Q

What regulates Bile acid

uptake in the ileum?

A

IBAT IBABP Ilial bile acit transporter ileal bile acid binding
protein both are FXR regulated

188
Q

Which HDL is taken back up

by the liver?

A

HDL 2

189
Q

What regulates cholestrol

synthesis?

A

HMG-CoA reductase

190
Q

What regulates
bile/cholesterol transport into
the bile canaliculi?

A

ABC transporters, ABCA1 ABCG1 BSEP

191
Q

What does LXR do

A

LXR stimulates bile acid synthesis, by activating 7-alphahydroxylase
Increases ABCA1, ABCG1 activity, increased bile
transport Activaters CETP Cholesterol Ester transfer protein,
Increasing cholesterol transfer into HDLs Mutations in CETP
increase atherosclerosis, and increasing activity increases
Cholesterol clearance

192
Q

What do insigs do?

A

INSIGs bind to SCAPs and prevent them from activating sterol

synthesis.

193
Q

What does FXR do?

A

Increases BSEP activity, increased Bile salt export pump.

Increases SHP activity, which inhibits LXR

194
Q

How is cholesterol synthesis
induced by low cholesterol,
in the liver?

A

SREBP-2, an ER-integral membrane protein SREBP-2 binds to
SCAP in the ER membrane, SREBP-2-SCAP complex moves to
the golgi and is cleaved SREBP-2 is cleaved into fragments which
go to the nucleus and bind DNA SRE, inducing increases HMGCoA
synthesis. Low cholesterol also increases LDL-receptor
expression to obtain fats.

195
Q

How is Cholesterol taken up

by peripheral cells?

A

By the LDL receptor

196
Q

How is cholesterol exretyed

by peripheral cells?

A

by ABCA1 ABCG1,5,8 Into HDLs Under control of the LXR

transcription factor.

197
Q

Antithrombotic mediators of

endothelial cells

A

PGI2 ADP

198
Q

Anticoagulant effect of

endothelial cells

A

Thrombomodulin Heparin

199
Q

Fibrinolytic effect of

endothelial cells

A

tPA PAI-1

200
Q

Cytokines establising smooth

muscle tone of the Aorta

A

NO Bradykinin

201
Q

Anti-inflammatory effect of

endothelial cells

A

Inhibition of adhesion and migration of leukocytes.

202
Q

Changes in expression by
dysfunctional endothelial
cells

A

Increased CRP decreased eNOS decreased NO Increased VCAM-
1, more leukocyte adhesion Increased MCP-1 monocyte and
macrophage chemotaxis

203
Q

Possible sources of ROS

A

Macrophages NADH/NADPH oxidase, Xanthine oxidase iNOS
Endothelial cells eNOS Lipoproteins sdLDL has low affinity for
LDL receptor and longer half life, thus more oxLDL. Lipid
peroxidation peroxidation of plasma membrane peroxidation of
LDL oxLDL

204
Q

How do macrophages
damage endothelium and
contribute to atheroma

A

Metalloproteases ROS Trapping in the endothelium Foam cell
generation sdLDL and oxLDL accumulation, Cholesterin crystals
necrosis

205
Q

Components of an atheroma

A

Dysfunctional/damaged endothelium overlying Macrophages,
Foam cells, Monocytes Fibroblasts Cholesterol Cholesterin
crystals Necrotic core Apotpotic cells Calcified cholesterols
Smooth muscle cells

206
Q

Atherosclerosis risk factors

A

High cholesterol, High LDL smoking Hypertension B6 vitamin
deficiency Hyperhomocysteinemia Obesity Diabetes
Hyperglyceima Hypertriglyceridemia

207
Q

What causes familial

hypercholesterolemia

A

LDL receptor mutations ApoA1 mutation, low HDL LCAT

mutation ABCA1 Cyp27 LPL deficiency is NOT a risk factor.

208
Q

Medical treatments for

atherosclerosis

A

Statins inhibit HMG-CoA reductase NPC1L1 inhibitors VLDL

exocytosis inhibitors PPAR activators, called fibrates.

209
Q

PPARalpha

A

inhibits SREBP-1 and SREBP-2 activation, thus inhibiting FA
synthesis and Cholesterol synthesis Also inhibits Malic enzyme,
inhibiting conversion of citrate to pyruvate and NADPH for
cholesterol synthesis. Decreases LDL receptor expression

210
Q

fference between just
immortalized cells and
transformed cells

A

Immortalized can replicate indefinitely, but don’t metastasize
within the animal, Still only grow in a monolayer and need
attachment, still subjected to contact inhibition Transformed
Immortalized and also are not subject to attachment or contact
inhibition, will proliferate while floating and in the absence of
growth facto

211
Q

Senescence

A

induced by telomere shortening or tumor suppressor factors

mainly, p53 or RB p53, activates p21 and disinhibits Rb

212
Q

multiple mechanisms how

p53 inhibits tumors

A

Prevents vascularization Causes cell cycle arrest and senescence
Initiates DNA repair pathways Induces Apoptosis

213
Q

DNA viruses that can inhibit

p53

A

HPV E6 inhibits p53 E7 inhibits Rb Adenoviruses inhibit p53 and
Rb SV40, simian vacuolating virus 40, a polyoma virus, other
polyoma viruses also inhibit p53 and Rb

214
Q

How does Rb inhibit

proliferation?

A

Binds to E2F transcription factors (a family of TFs), preventing
them from activating cell cycle genes.

215
Q

What are the proteins that
specifically inhibit p53 from
those viruses?

A

E6 from HPV LT E1B

216
Q

What do the adenoviral

proteins E1A and E1B inhibit?

A

E1A inhibits RB E1B inhibits P53

217
Q

what are 3 ways tumor cells

bypass senescense

A

inhibiting p53 inhibitin Rb Expressing telomerase

218
Q

What RNA viruses are

tumorviruses?

A

Retroviruses, by integration of oncogenes into genome. Rous

Sarcoma Virus HTLV-1

219
Q

What is the oncogene in

Rous Sarcoma Virus

A

v-src, which is a mutated version of the somatic c-src non-receptor
tyrosine kinase. c-src is a normal host proto-oncogene. induces
motility, proliferation, survival.

220
Q

What kind of proteins are

coded by human protooncogenes?

A

Growth factors Tyr Kinase receptors Intracellular signaling
proteins, non-receptro tyroskine kinases ser/thr kinases
Transcription factors Nuclear TF receptors, Positive cell cycle
regulators, cyclins Inhibitors of Apoptosis, BCL2

221
Q

How do protooncogenes

become oncogenes

A

By activating mutations, basically list any way a mutation can
increase gene activity. Point mutations Gene amplification
Chormosomal translocation, different regulation, increased
expression Deletions or repressor regions Insertion of a viral DNA
hyperactive promoter region in front of the gene.

222
Q

How can Ras be permanently

activated via mutation

A

A point mutation that changes Gly -> Val Ablates its GTPase
activity, thus it binds GTP becoming active and then never cleaves
it to GDP to inactivate itself.

223
Q

Human tumor viruses

A

EBV HBV, HCV HTLV-1 HPV many strains Kaposi sarcoma virus

Merkel cell polyomavirus

224
Q

Random animal tumor

diseases

A

Tasmanina devil facial tumor disease, trasmitted by biting Canine
tranjsmissible veneral tumors

Pathobiochemistry (1 decks)

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