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Metabolic Basis of Disease > Midterm 3 > Flashcards

Midterm 3 Flashcards

1
Q

Risk factors for NAFLD

A

Non alcoholic fatty liver disease - risk factors include: age, obesity, female gender, hispanic ethnicity, viral hepatitis, iron overload

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2
Q

NASH

A

Non alcoholic steato hepatitis: inflammation leads to scarring/hardening of liver (fibrosis) which kills liver cells (cirrhosis)

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3
Q

Mechanism by which obesity causes de novo lipogenesis and can lead to fatty liver

A

Obesity leads to insulin resistance which causes hyperinsulinemia which –> p-ACC –> malonyl CoA increase (which is the basis for fatty acid synthesis)

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4
Q

Mechanism by which obesity causes TG synthesis (and leads to fatty liver)

A

Obesity leads to insulin resistance which causes hyperglycemia –> chREBP –> TG synthesis (de novo lipogenesis promotes TG synthesis and FA oxidation downregulates it)

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5
Q

Management of NAFLD

A
  1. Lifestyle modification (diet & exercise) 2. Weight loss medications 3. bariatric surgery 4. specific NASH drug therapy
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6
Q

ALT

A

enzyme used to detect liver injury

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7
Q

Perilipin

A

regulates lipid droplet accumulation and lipolysis

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8
Q

Process that leads to NASH

A

Lipid droplet gets too big and warps liver cell, warping affects blood flow and reduces oxygen supply, macrophages (kupffer) recruit more immune cells and inflammation –> collagen build up and fibrosis

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9
Q

Characteristics of fatty liver disease

A

increase in dietary fat, increase in de novo lipogenesis –> increase TG synthesis, also decreased VLDL formation, decreased beta oxidation and decreased lipolysis

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10
Q

Factors that cause NAFLD and NASH respectively

A
  1. obesity, overnutrition, inactivity, genetic factors 2. inflammation (metabolites from microbiota and adipokines from adipocytes) ER stress and oxidative stress
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11
Q

Sarcopenia

A

progressive loss of skeletal muscle mass and strength with risk of adverse outcomes (disability, etc.) especially due to age

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12
Q

How do muscle fibers change in sarcopenia

A

1) Decreased muscle fiber size- atrophy, 2) decreased number of muscle fibers and 3) selective loss of type 2 fibers

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13
Q

Causes of sarcopenia

A

Age, disuse, cachexia, neurodegenerative disease, endocrine, nutrition malabsorption

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14
Q

what happens to muscle weight, muscle fiber size and number of muscle cells in sarcopenia?

A

All decrease

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15
Q

What decreases in sarcopenia?

A

Muscle weight, type 1 fibers, ESP type 2 fibers, muscle fiber size, muscle cell numbers, muscle stem cells, power produced, anaerobic activity, mitochondrial function and contraction time

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16
Q

What increases in sarcopenia?

A

Myostatin (which decreases muscle growth and differentiation) and lactic acid consumption

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17
Q

Prevention of sarcopenia

A

Exercise, increase dietary protein intake, supplement protein after exercise

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18
Q

Sources of arachidonic acid

A
  1. membrane phospholipids and 2. dietary intake of omega-6s
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19
Q

Differences between type 1 and type 2 muscle fibers in fuel burned, contraction time

A

TG vs. ATP and creatine, slow vs. fast

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20
Q

Proinflammatory products coming from omega-6s/arachidonic acid

A

eicosanoids, prostaglandins, leukotrienes, thromboxanes

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21
Q

Anti-inflammatory products coming from omega-3s

A

resolvins, protectins and eicosanoids (minimally inflammatory, degrade more rapidly than omega 6 eicosanoids)

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22
Q

4 pathways metabolize arachidonic acid

A

cyclic pathway, linear pathway and cytochrome p450 pathways (hydroxylase and epoxygenase)

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23
Q

Products of cyclic pathway

A

synthesis of prostaglandins, prostacyclins and thromboxanes: many of them are pro-inflammatory mediators or play a role in metabolic disorders

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24
Q

Important enzymes of cyclic pathway

A

Thromboxane synthase, COX1 and COX2

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25
Q

PLA2

A

enzyme that releases HUFAs (arachidonic acid) from membrane

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26
Q

KO of PLA2

A

KO decreases adiposity

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27
Q

COX1

A

necessary for homeostatic functions like GI tract, or kidney function (inhibition undesirable)

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28
Q

COX2

A

inflammation (inhibition desirable) also sensitizes pain receptors and cancer risk - transcription of COX2 is stimulated by cytokines and growth factors

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29
Q

Corticosteroids

A

inhibit PLA2

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30
Q

NSAIDS

A

inhibit COX, divert substrates to LOX and Cyp

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31
Q

Products of linear pathway

A

Leukotrienes - many are involved in inflammatory and metabolic disorders

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32
Q

Important enzymes of linear pathway

A

LOX (lipooxygenase)

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33
Q

Products of cytochrome P450 pathway (hydroxylase)

A

20-HETE - involved in inflammation and hypertension

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34
Q

Products of cytochrome P450 pathway (epoxygenase)

A

EETs - good metabolite, improve wound healing and reduce inflammation, decrease pain, increase organ regeneration

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35
Q

Hydroxylase

A

converts arachidonic acid to 20-HETE in Cyp 4 pathway (smooth muscle)

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36
Q

Epoxygenase

A

converts arachidonic acid to EETs in Cyp 2 pathway (astrocytes)

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37
Q

sEH

A

enzyme that degrades EETs

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38
Q

PLA2, COX1 and COX2 all prefer _____

A

omega 6’s over omega 3

39
Q

Which are neutral to omega 3 or omega 6?

A

phospholipid synthesis enzymes and linear and cytochrome 450 pathways

40
Q

How can a diet high in omega-6 lead to obesity? (2 ways)

A

1) increased phospholipids so increased arachidonic acid –> cyclic pathway –> PGE2 which binds to EP3 receptor which suppresses cAMP production, decreases lipolysis which leads to increased fat accumulation –> obesity
2) phospholipids –> higher AA –> higher 2AG and AEA which binds to cannabinoid receptor and leads to increased food intake, fat storage and inflammation

41
Q

PGE2 (and KO)

A

prostaglandin that is product of cyclic pathway, KO of PGE2 causes decreased adiposity (increased lipolysis and FAO)

42
Q

CB1R

A

Cannabinoid receptor

43
Q

2AG and AEA

A

increase appetite, increase fat storage/obesity and inflammation, decrease fatty acid oxidation (bind to cannabinoid receptor)

44
Q

Caloric restriction

A

undernutrition without malnutrition (reduced calories, adequate nutrients) and seems to lead to increased health span

45
Q

Benefits of caloric restriction

A

Decreased blood glucose and insulin levels, decreased risk of insulin resistance/diabetes, heart disease and cancer, decreased oxidative damage and inflammation…

46
Q

Negative effects of caloric restriction

A

Increased hunger, erratic temperament, decreased libido, decreased bone and muscle density, immunosuppression

47
Q

AMPK

A

sensor of low energy that promotes glucose transport, fatty acid oxidation

48
Q

mTOR

A

stimulates translation - regulates growth and cell division

49
Q

Sirtuins

A

genes that regulate metabolism and mitochondrial function, stimulated by CR

50
Q

Sestrins

A

activate AMPK

51
Q

IGF-1 signaling

A

stimulates growth and advances aging, CR antagonizes the IGF receptor

52
Q

Cell response to CR

A

cell fitness and longevity: autophagy, stress defense mechanisms while attenuating inflammation and growth

53
Q

Metformin

A

activates AMPK so promotes CR-like transcriptional changes

54
Q

Rapamycin

A

inhibits mTOR, extends life span in mice only

55
Q

Resveratrol

A

activates sirtuin and AMPK - promotes healthy aging

56
Q

Genetic variant that 95% of celiac patients have

A

HLA DQ2 or DQ8

57
Q

Gliadin

A

Protein fraction of gluten, highly toxic

58
Q

tissue transglutaminase

A

converts gliadin into deamidated peptide (even more toxic)

59
Q

NOD2

A

gene that when mutated is associated with Crohn’s disease (only 25% of Crohn’s disease patients have mutations)

60
Q

Triggers of IBD

A

environment, genetics, intestinal microbiota, immune response irregularities

61
Q

Crohn’s disease mechanism

A

normally intestinal microflora trigger NOD2 to trigger NF-kB and defensins are released, however if paneth cells have mutated NOD2, then NF-kB is not triggered and defensins are not released, leading to bacterial overgrowth

62
Q

Defensins

A

small peptides that kill bacteria

63
Q

Treatments for IBD (not celiac disease)

A

glucocorticoids, free radical scavengers, antibiotics, PXR agonists

64
Q

PPARalpha

A

catalyzes fatty acid oxidation, anti-inflammatory

65
Q

PPARgamma

A

reduces hyperglycemia and promotes pre-adipocyte differentiation

66
Q

PPARbeta/delta

A

anti-inflammatory effects by inhibiting NF-kB

67
Q

Aerobic glycolysis

A

Warburg effect - cancer cells switch to less efficient metabolism that results in 4 ATP

68
Q

Oxidative phosphorylation

A

Normal metabolism - results in ~36 ATP

69
Q

Why do cancer cells switch to less efficient metabolism?

A

They may need other metabolic intermediates more than ATP, nutrients are shifted away from energy metabolism to support cell proliferation

70
Q

Glucose is used by cancer cells for:

A

Making acetyl-coA (fatty acids), non essential amino acids, ribose for nucleotides

71
Q

Lipid metabolism in cancer

A

Tumor load promotes breakdown of lipids in adipose tissue in cachexia, also stimulates fatty-acid synthesis –> lipids support cell growth, proliferation etc

72
Q

Reductive carboxylation

A

glutamine is converted to citrate which can be used to form lipids through reverse TCA cycle

73
Q

Carcinogenic compunds

A

heterocyclic amines, nitrosamines and aflatoxin

74
Q

Chemopreventative compounds

A

Isoflavones, indoles, polyphenols

75
Q

Obesity contributes to cancer risk

A

by increasing insulin secretion and availability of IGF1 due to increased production of IGF binding protein

76
Q

Hormonally active form of vitamin D aka calcitriol

A

1,25 dihydroxycholecalciferol

77
Q

1 alpha hydroxylase

A

converts vitamin D prohormone into active hormone

78
Q

Source of vitamin D

A

diet, sunlight (half life 1 day)

79
Q

Source of prohormone 25-OH-D

A

liver (half life 3 weeks) - blood test for this

80
Q

Source of active hormone 1,25,(OH)2D

A

kidney (half life 2 hours)

81
Q

vitamin D prohormone enters cell via

A

megalin-cubulin mediated endocytosis

82
Q

vitamin D enters cell via

A

diffusion

83
Q

Process by which vitamin D influences immune response

A

TLR binds a pathogen, TLR increases 1alpha hydroxylase and VDR expression, 25(OH)D enters cell and converted to active form so it can bind to VDR –> VDR transcribes antimicrobial peptides (defensins and hCAP) which target and kill pathogen

84
Q

Toll-like receptors (TLR)

A

Pattern recognition receptors which recognize conserved molecular patterns of microbial pathogens

85
Q

Innate immune response

A

non-specific immune response with pattern recognition receptors and production of antimicrobial peptides

86
Q

VDR negatively regulates its own activity by:

A

increasing production of enzyme that degrades active vitamin D, down regulation of TLR and down regulation of NF-kB

87
Q

Angiotensinogen

A

Produced in the liver and acted upon by renin to produce angiotensin 1

88
Q

Renin

A

produced in the kidneys and acts upon angiotensinogen

89
Q

Angiotensin converting enzyme

A

found in the lungs and converts angiotensin 1 to angiotensin 2

90
Q

Aldosterone

A

converted from angiotensin 2 in the adrenals, acts on heart to increase heart rate and on blood vessels - vasoconstriction - both increase blood pressure.. also signals kidneys to retain water and sodium

91
Q

ANP

A

opposite effect of aldosterone, lowers blood pressure

92
Q

MR (mineralocorticoid receptor)

A

receptor for aldosterone (which is the main mineralocorticoid - steroid hormone that influences salt and water balance)

93
Q

AT1R

A

main receptor in RAAS

Metabolic Basis of Disease (3 decks)

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