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Medical Biochemistry and Pathophysiology > Week 4B: Histopathology Pancreas, Regulation Gene Expression, Nuclear Hormone Receptors & Iron Metabolism > Flashcards

Week 4B: Histopathology Pancreas, Regulation Gene Expression, Nuclear Hormone Receptors & Iron Metabolism Flashcards

HC27-29

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USMLE® Step 1 flashcards
1
Q

Keratin in skin

A

-Subaceous glands (talgklieren)
-Epithelium cells (plaveisel)
-Hair follicles
-Sweat glands

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2
Q

From which germ later are the endocrine cells of the pancreas (islets) derived?

A

Endoderm

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3
Q

Secretion in pancreas

A

-Exocrine: to lumen duodenum through duct
-Endocrine: give hormones to blood

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4
Q

Formation pancreas out of endoderm

A

Pancreas is a bulge (uitstulping) of primary endoderm tube, but contact with for islets outside world was lost during embryogenesis.
> can differentiate back
> Islets are epithelial cells

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5
Q

HE staining acini of exocrine pancreas: blue on basal cytoplasm (nucleic acids) and red on apical side (protein)

A

Mitochondrial DNA but a lot of ribosomes with rRNA at basal cytoplasm for production of enzymes
> made as zymogens

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6
Q

Enzyme production in pancreas types

A

-Zymogens like trypsinogen
-Active enzymes like lipase (needs cofactor, not immediately active), alpha-amylase

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7
Q

Pancreatic ductal epithelium make a lot of water and bicarbonate, why?

A

To rise the pH from incoming acidic food in duodenum (neutralize)
> apical granules for secretion

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8
Q

How well are islets vascularized compared to exocrine pancreas?

A

not very distinct
> portal vein structure of blood flow in pancreas
> oxygen use of one part influences potential to use oxygen for downstream part

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9
Q

The best vascularized endocrine pancreatic cells are the

A

beta cells

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10
Q

Why gap junctions in islets of Langerhans?

A

Connects cytoplasms
> calcium waves released upon increased ATP/ADP ratio > processing glucose through GLUT2 increases insulin secretion through gap junction. > quick transduction signals
Protects cells against symptoms diabetes mellitus
- sensitive cells

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11
Q

Functions tight junctions

A

Sorting proteins to PM, and regulate permeability of epithelium (diffusion barrier)

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12
Q

Streptozotocine can target endocrine pancreatic cells, how?

A

Partly glucose analog > through GLUT2
Has nitrosurea group (urea connected to nitroso group (R-NO) > DNA alkylating agent > toxic for DNA
> also: depletion NAD+ and oxidative stress
> damaged beta cells > autoantibodies
> DM in mice
> ratio alpha/beta cells to 50/50 from 5/95 in healthy
> beta cells affected: take up glucose

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13
Q

Are there active beta cells in DM?

A

Yes, but DM has threshold vale

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14
Q

Measuring insulin production

A

C-peptide levels
> insulin made as large pro-hormone by pancreas
> Oxidation of the large C-peptide > 2 intra chain disulfide bonds formed and one exra intra chain linkage disulfide (disulfide bonds in the mature insulin (A and B chains) > hydrogen peroxide made > oxidative stress when too much

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15
Q

Insulomas make much

A

insulin

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16
Q

Do insulomas of alpha cells exist

A

yes

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17
Q

Interactions that regulate secretion of insulin an and glucagon

A

-Plasma glucose
-Neurons > synaptophysin (neuroendocrine cells)
-Autonomous regulation of islets in neuronal

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18
Q

Beta cells take up glucose through GLUT2 and make insulin to inhibit the cAMP and PKA signaling in alpha cells to secrete glucagon release. Other regulations

A

-Parasympatic neurons can activate it (activated through glucose)
-Adrenaline can bind beta-adrenergic regulation: stimulate glucagon secretion
-Pancreatic islet delta cells take up glucose through GLUT1,3 and insulin binding by SGLT2 > Somatostatin binds receptor on alpha cells: inhibit cAMP and glucagon secretion.
-Glucose uptake through GLUT1/3 by alpha cells

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19
Q

Epsilon cells of pancreas make the hunger hormone:

A

Ghrelin

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20
Q

Stages of T1DM

A

1: beta cell autoimmunity but still normoglycemia and presymptomatic
2: dysglucermia and presymptomatic
3: symptomatic

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21
Q

Pancreatitis

A

exocrine pancreas damaged: autoinflammation
> islets not targeted

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22
Q

HC28: Hierarchy of metabolic regulation

A

Top down >
- Transcription-translation
- Expression isozymes or isotypes
- Protein synthesis/breakdown
- Proteolytic activation
- PTMs like phosphorylation
- Allosteric control by metabolites
< Bottom up

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23
Q

Regulating steps gene expression

A

-Transcriptional control
-RNA processing control
-RNA transport control
-Translation control protein activity control

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24
Q

Gene expression profiles reflect:

A

Function of organs
like exretion digestive enzymes by pancreas and lipid transport by liver

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25
Q

Nucleosome

A

Complex formed by histone octamer and 145 bp DNA fragment

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26
Q

Histone octamer

A

(H3)2(H4)2 tetramer and pair of H2A-H2B dimers

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27
Q

Epigenetic regulation of chromatin accessibility

A

-DNA methylation
-Histone modification (acetylation, methylation)

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28
Q

Compact chromatin effect

A

Block gene expression

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29
Q

Promotor

A

DNA stretch located in front of transcription initiation, where RNA polymerase II will bind.

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30
Q

DNA methylation effect on transcription

A

Makes heterochromatin > correlated with methylation of cytosines in DNA

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31
Q

Which enzyme methylates cytosines in DNA?

A

DNA methyl transferases

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32
Q

Which parts of histones are modified?

A

The tails

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33
Q

General principle methylation and methylation of histone tails

A

-Acetylation of lysines (K): activation

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34
Q

Trimethylation of histone tails occurs at ?

A

Promotors for repression

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35
Q

Histone acetylation means … and is done by…

A

Activation
> Histoen acetyltransferases (HATs)
> Catalyze the transfer of acetyl-groups of acetyl-CoA to specific Lys residues in amino terminal tails of histones
> costs energy: acetyl-CoA with energy rich thioester bond

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36
Q

Which enzymes deacetylate histone tails?

A

Histone deacetulases (HDACs)

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37
Q

Why does acetylation of histones promote gene expression

A

-DNA is negatively charged (phosphate group) and histones positively charged: tight packaging
-Acetylation reduced number of positively charged groups on histones and weaken strength of interaction with negatively charged DNA
> promoter / enhancer becomes more accessible

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38
Q

Are HATs and HDACs specific for histone tails?

A

No, they can acetylate lysines of proteins, also of transcription factors which leads to either activation or inactivation

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39
Q

HATs aid TFs like … to increase chromatin accessibility to increase gene expression

A

CREB

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40
Q

CREB signaling in liver

A

Fasting: glucagon rules
> Glucagon binds
> cAMP and PKA singaling
> PKA phosphorylates CREB (CRE binding protein)
> HAT (CREB bound after activation) acetylates histone and opens up the CRE (cAMP response element)
> CREB binds CRE
> transcription CRE regulated genes

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41
Q

CRE activated genes

A

Gluconeogenic genes
> PEPCK
> G6P > for glucose-6-phosphatase

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42
Q

In which gluconeogenesis signalling is HDAC involved?

A

FoxO1

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43
Q

FoxO1 signalling when insulin rules (high glucose)

A

Insulin binds receptor
> activation PKB/Akt through signal transduction
> Akt/PKB phosphorylates FoxO1 and bound HDACs in cytosol
> FoxO1 and HDACs dissociate after FoxO1 is acetylated > no transcription

44
Q

Response element

A

DNA element that can be bound by TFs
mainly enhancers

45
Q

FoxO1 signaling when no insulin

A

Inactive acetylated FoxO1 is deacetylated by active HDACs (dephosphorylated) and FoxO1 becomes active and promotes gene expression of gluconeogenic genes like PEPCK and G6P

46
Q

Transcription factor families

A

-Leucine zippers
-Helix turn helix
-Zinc fingers

47
Q

Transcription factors are the smart bullets which need co-activators. Explain.

A

TFs are the only molecules who know where to bind DNA
> Example co-activator is the Mediator
> co-activator are regulated by phsophorylation

48
Q

Mediator function

A

Bind TFs and RNA pol II, forming a ‘bridge’
> binding of mediator to TFs helps recruit RNA pol II

49
Q

Most disease SNPs are in

A

Enhancers

50
Q

Enhancer sequences

A

DNA sequences without promoter activity but can increase transcription even when located far away (1000s)
> serve as binding sites for signal/tissue specific transcription factors
> DNA binding proteins influence transcription initiation by altering local chromatin structure to expose gene or its regulatory sites (co-activators)

51
Q

Islet-1

A

TF with important role in developing nervous system
> assay with reporter construct which connects with GFP

52
Q

Transcription initiation regulation

A

-Folding of DNA brings TFs at enhancer into contact with transcription initiation complex
> transcription of human genes regulated by collaborating TFs which integrate all signals

53
Q

TF SREBP2 promotes

A

Cholesterol biosynthesis and cholesterol uptake

54
Q

TF LXR promotes

A

Cholesterol efflux

55
Q

Eukaryotic TFs have multiple … and … domains

A

DNA binding and activation
> required to activate expression of most genes
> most TFs bind enhancers, some promoters
> bind through specific motifs in DNA

56
Q

SREBP2 pathway

A

Cells are deprived of cholesterol
> Scap escorts SREBP from ER to Golgi
> In Golgi: S1P and S2P cleave TFs from transmembrane domain and release to nucleus to bind SRE and activate gene expression
Cells high cholesterol
> Trigger binding of Scap to Insig in the ER, transport SREBP to Golgi is blocked, no transcription

57
Q

Which genes are activated by SREBP2

A

LDLR and HMGCR (HMG CoA reductase) genes, cholesterol uptake and synthesis

58
Q

Insulin accepts another SREBP. Which one and what is the response?

A

SREBP1c
> in fed state
> Insulin releases Scap-SREBP from Insig
> SREBP1c activates FA synthesis genes ACC and FAS (Acetyl-CoA synthetase and Fatty acid synthase)

59
Q

LXR pathway

A

High cholesterol in cell
> LXR + RXR already bound to response element, but bound by co-repressors at first
> Activated by oxysterols or synthetic ligands: binding co-activators after that
> transcription of genes like ABCA1 which is needed in cholesterol effluc

60
Q

Which activators bind RXR and LXR

A

RXR bound by 9-cis retinoic acid
LXR bound by oxysterols or synthetic ligands

61
Q

RNA processing control of Apolipoprotein B

A

ApoB100 > synthesized in liver for VLDL, full length protein
ApoB48: in intestines for chylomicrons
In ApoB48: the translation is stopped earlier
> a deaminase in the intestine converts the cytosine of codon 2153 int uracil, to make stop codon premature.

62
Q

HC29: How large is the family of nuclear hormone receptors? How do they differ?

A

48 nuclear hormone receptors
> different substrate binding sites and DNA binding sites

63
Q

Nuclear hormone receptor general principle

A

-Respond to binding of hormones in cytosol (steroid hormones which can pass PM)
-Activation and translocation to nucleus to bind response elements

64
Q

Why can steroid hormones pass the PM?

A

They are amphipathic, can wiggle through PM

65
Q

What if a hormone X is hydrophobic completely, can it pass the PM?

A

No, it would get stuck.

66
Q

GRE

A

Glucocorticoid response element
> an enhancer
> activate program of genes through transcription initiation complex and DNA folding to the promoter and RNA pol II binding etc.

67
Q

Human steroid hormones

A

-Estradiol (an estrogen)
-Progesterone
-Testosterone
-Aldosterone
-Calcitriol (active vitD)
-Cortisol

68
Q

Most steroid hormones are …

A

amphipathic 3-oxo-sterols

69
Q

All steroid hormones are derived from…

A

Cholesterol
> OH group cholesterol is hydrophilic and the rest hydrophobic inclusive carbon tail
-In steroid hormones, sides switched, carbon tail becomes hydrophilic and the rings with the now ketone (=O, was OH) group is hydrophobic.

70
Q

Zinc finger TFs stick into…

A

the major groove of DNA

71
Q

Estrogen receptor activation

A

-Binding estrogens like estradiol
-Zinc finger motifs bind DNA (zinc based domains)
-Ligand binding domain in Helix-12
-Binds as dimer

72
Q

Conformational change estrogen receptor after binding ligand

A

Before: Helix-12 points outward, bound to inhibitory protein
after: points inward > activation > binding co-activator protein and DNA binding domain can bind DNA (the response element)

73
Q

Tamoxifen treatment

A

Against breast cancer > the tumor cells express estrogen receptor and depend on pathway for growth.
> Tamoxifen inhibits transcription of genes regulated by estrogen and reduces secretion growth factors
> Tamoxifen is antagonist of estrogen receptor

74
Q

Mechanism of action of Tamoxifen

A

In estrogen receptor-tamoxifen complex, tamoxifen extends from hydrophobic (ligand binding) pocket, preventing the co-activator from binding and inhibiting gene expression
> antagonist estrogen receptor

75
Q

Tamoxifen is a prodrug, how is it activated

A

CYP2D6 and CYP3A4 metabolize tamoxifen into the active 4-hydroxy-tamoxifen
> hydroxylate: add OH group
> make drug more water soluble because then recognized as foreign for excretion, but activates the antagonist

76
Q

Anabolic steroids and the androgen receptor

A

Steroid hormones (androgens) bind androgen receptor
> binding receptor enhances gene expresion for development of muscle mass
> Anabolic steroids are agonists of androgen receptors which resemble androgens

77
Q

Glucocorticoid receptors activate a gene … by binding the activating ….

A

gene program by binding the steroid

78
Q

Cortisol and the glucocorticoid receptor

A

Chronic stress hormone (works slower than adrenline, through gene expression)
> released upon fasting and chronic stress by adrenal gland cortex (adrenaline in medulla)
> less peaks during day

79
Q

Glucocorticoid receptor ligands incl drugs

A

-Hydrocortisone (cortisol) works as anti-inflammatory and immunosuppressive drug to control inflammation in dermatitis and rhematism
-Prednisone is converted in liver to active drug prednisolone
-Prednisolone is 4 times more patient than hydrocortisone
-Dexamethasone is 30 times more potent than hydrocortisone

80
Q

Glucocorticoids bind the glucocorticoid receptor (GR) > act slow via gene expression > which genes ?

A

Causes precursors of gluconeogenesis (glycerol and amino acids) to move o liver, where they are converted to glucose and stored to glycogen.
> similar effect as glucagon / adrenaline (but glucagon induces glycogen breakdown)

81
Q

Side effects glucocorticoids

A

Osteoporosis

82
Q

Effects cortisol

A

-Lipolysis in adipose tissue stimulated
-Protein degradation in muscle stimulated and synthesis inhibited
-Gluconeogenesis stimulated
-Glucose levels increase
-Beta oxidation stimulated
-Suppression immune response
-Promote glycogen formation (glycogen breakdown is then stimulated by adrenaline)
> fasted state responses

83
Q

Long term treatment with glucocorticoids (GCs)

A

-Like untreated T1DM, but with them the glucagon is extremely high because insulin is absent
-State of starvation
> Proteolysis up
> Gluconeogenesis up
> blood glucose up
> insulin in plasma up
» glycogen synthesis up
» fat synthesis up
(breakdown arm and leg muscles for gluconeogenesis)
> lose muscle, gain fat

84
Q

PPAR nuclear hormone receptors work with another nuclear receptor to form heterodimers. Which?

A

RXR (retinoid X receptors)

85
Q

Activation PPAR

A

PPAR has ligand binding/dimerization domain, DNA binding domain and transactivation domain
> 9-cis retinoic acid (made from vitamin A) activates RXR

86
Q

Vitamin A forms

A

-Retinol (COOH group)
-Retinal
-Retinoic acid > activates RXR

87
Q

Function PPAR-alpha and PPAR-gamma

A

PPAR-alpha (liver) > burn fat
PPAR-gamma (adipocytes) > store fat

88
Q

Ligands of PPAR-alpha nuclear receptors

A

-Free fatty acids (FFAs)
-Eicosanoids (C20)
-Fibrates (drugs)

89
Q

Fibrates

A

Lipid lowering drugs for hypertriglyceridemia
> prodrug: ester bond first hydrolysed (OH hydroxyl end left)
> analog of FAs

90
Q

Target genes PPAR-alpha

A

Upregulation of genes encoding
> CPT-1
> Very-long/medium chain acyl-CoA dehydrogenase (VLCAD/MCAD)
> HMG-CoA synthase
-So beta oxidation upregulated (and more ketone bodies)
> TAG levels in plasma down
> LPL up > VLDL and TAG in plasma down
> Apo-A1 > HDL up (made in liver and takes up cholesterol in periphery)

91
Q

Ligands PPAR-gamma receptors (adipocytes)

A

-FFA unsaturated
-Eicosanoids (C20)
-Thiazolidinediones (TZDs)

92
Q

TZD (glitazones)

A

Drugs for T2DM
> pioglitazone and rosiglitazone used today
> Thi (S)-axolidine (ring with NH in it) -dione (two ketone groups to carbons) > functional group

93
Q

Target genes PPAR-gamma

A

-LPL: lipoprotein lipase
-FATP, CD36: FA transporters
-Acyl-CoA synthetase: FA esterification to prevent efflux

94
Q

Effects PPAR-gamma activation

A

-Adipocyte differentiation
-Lipid synthesis (lipogenesis)
-TAG levels in plasma and liver down
-Anti-inflammatory
> Insulin resistance down

95
Q

Side effects PPAR-gamma

A

-adipocyte differentiation, lipogenesis and less TAG in plasma and liver induces obesity
> change of diet needed

96
Q

TZDs cause lipid redistribution from … to …

A

Abdominal to subcutaneous adipose tissue

97
Q

Cirrhosis in liver disease characterized by ectopic fat deposition

A

Steatosis (fatty liver) > hepatitis (inflammation) > fibrosis (scarring) > cirrhosis (liver damage)
-Cells die because of too much fat > inflammation and scarring

98
Q

Translational control of iron metabolism

A

IRP (iron responsive element binding protein) can bind either ferric iron in cell (Fe3+) or the IRE (stem loops structure) in the mRNA of both ferritin and transferrin receptor
Much iron
> IRP binds Fe3+
> IRP does not bind the IRE in 5’-UTR of ferritin mRNA, it is not blocked from translation: expression
> IRP does not bind IRE in 3’-UTR of transferrin receptor mRNA, not stabilized, degradation mRNA, no translation
Depletion Iron
> IRP binds IRE: blocks ferritin mRNA translation and stabilizes transferrin receptor mRNA molecule and translation (more iron uptake)

99
Q

Iron as a double-edge sword

A

-It is essential for the function of hemoglobin and many enzymes like the electron transport chain complexes with Fe-S clusters and CYP enzymes
-Too much is toxic: Fenton reaction generates ROS which initiates ferroptosis (cell death)

100
Q

Why translational control of iron regulating proteins?

A

Quick response, ready to go mRNA
> needs to be finetuned precisely without much fluctuation

101
Q

Iron in body

A

-65% bound to hemoglobin in erythrocytes (reversible binding O2)
-Myoglobin in muscle (reversible binding O2)
-Storage of iron by ferritin in most cells (30%)
-Iron transport by transferrin in blood (0.7%)

102
Q

How is iron-bound transferrin taken up by cells expressing the transferrin receptor

A

Receptor-mediated endocytosis
> lumen of endosome acidifies by influx H+
> Iron released and transported to cytosol via transporter
> Tranferrin releases receptor
> Exocytosis: receptor back on surface and transferrin recycled to blood to bind iron

103
Q

Why storage iron by ferritin

A

Free iron is toxic and needs to be stored safely
> 24 ferritin proteins in big spherical shell
> in cytosol
> in equilibrium with low concentration of free iron

104
Q

How is the regulation of ferritin and transferrin receptor in the cell by IRP called?

A

Reciprocal regulation
> one regulatory protein controls translation of two different mRNA in reciprocal manner

105
Q

Nuclear receptor to transcription

A

NR - ligand binding - co-activator - HAT - DNA unwinding - transcription

106
Q

PPAR-alpha vs PPAR-gamma in drugs

A

fibrates vs TZDs
Burn fat vs store fat

Medical Biochemistry and Pathophysiology (16 decks)

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