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GER UNIT 8 > MCP > Flashcards

MCP Flashcards

1
Q

sitosterolemia

A

mutations in genes encoding sterolin 1 and 2 transporters→decreased pumping of phytosterols back to intestine→imparied ability of liver to excrete phytosterols into bile→increased phytosteroil in blood and tissues

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2
Q

synthesis of cholesterol

A
  • in all cells except RBCs
  1. Actyl CoA→HMG CoA
  2. HMG CoA→mevalonate by cytosolic HMC CoA reductase (rate limiting step)
  3. mevalonate (6C) to cholesterol through series of phosphorylations via 5C, 10C, 30C intermediates
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3
Q

what are the ways in which HMG CoA reductase is regulated?

A
  • transcriptional regulation: cholesterol binds SCAP and sequesters complex in ER→decreased enzyme
  • post translational regulation: enzyme triggers it ubiquitination
  • direct regulation: de/phosphorylation
  • hormonal regulation: insulin and thyroxin upregulate, glucagon and glucocorticoids downregulate
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4
Q

statins

A

structural analogs of HMG that competitively inhibit HMG CoA reductase→lower plasma levels of cholesterol

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5
Q

bile acids vs. bile salts

A
  • salts (deprotonated)
  • acids (protonated); conjugated to glycine or taurine before leaving liver (increases amphipathic nature/better detergent)
  • in 1:1 ratio in duodenum because their pKa=pH=6
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6
Q

what is the rate-limiting step of bile acid synthesis?

A
  • addition of hydroxyl group at C7 of cholesterol→7-a-hydroxycholesterol
  • (downregulated by bile acids)
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7
Q

what is the importance of dual secretion process whereby movement of cholesterol into bile is accompanied by bile salt and phospholipid secretion?

A

if dual secretion process is disrupted, cholesterol cannot be sufficiently solubilizated by bile salts and phospholipids→precipitation of cholesterol and formation of gallstones

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8
Q

structure of lipoproteins

A
  • inner hydrophobic core of TAG and cholesterol esters
  • shell of amphipathic phospholipids, includes unesterified cholesterol and apolipoproteins
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9
Q

chylomicron metabolism

A

small intestine with ApoB48→ApoCII and ApoE from HDL→lipoprotein lipase cleaves it into FA and glycerol→ApoCII is returned to HDL→chylomicron remnant binds through ApoE to liver and is endocytosed

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10
Q

VLDL metabolism

A

liver→nascent particles with ApoB100→ApoCII and ApoE from HDL→cholesterol ester transfer protein (CETP) exchanges TAGs from VLDL to HDL in return for cholesterol esters→TAG degraded by LPL→VLDL convered to LDL in blood with IDL (VDLD remnants)→ApoCII and ApoE returned to HDL

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11
Q

HDL

A
  • serves as circulating supplier of ApoCII and ApoE
  • reverse cholesterol transport: efflux of cholesterol from peripheral tissue to HDL, esterification by LCAT, binding of cholesterol ester rich HDL2 to liver transfer of cholester ester to hepaocytes
    • high HDL is protective against atherosclerotic plaques because of this activity
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12
Q

how does LDL receptor assist cellular uptake of blood lipoproteins?

A

translation is coordinately regulated with HMG CoA reductase expression by supply level of cholesterol; has 6 regions:

    1. LDL binding
    1. where pH dependent conformational change occurs
  • 3&4. make receptor accessible for LDL
    1. single pass through bilayer
    1. associates with clathrin, initiates endocytosis when LDL is bound
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13
Q

what is the role of lipoproteins in CVDs?

A

macrophages have scavenger receptors that endocytose oxidative damaged LDL, become foam cells→recruit cytokines→migrate smooth muscle from media to intima where they proliferate and secrete plaque matrix that thin fibrous cap until rupture and expose contents to procoagulants→thrombus

  • high LDL correlates with increased likelyhood of artherosclerotic plaques
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14
Q

what is the rate limiting step in steroid hormone formation?

A

conversion of cholesterol to pregnenolone by cholesterol desmolase (located on IMM)

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15
Q

congenital adrenal hyperplasias

A

deficiencies in enzymes of steroid synthesis→build up of substrates/diminished products

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16
Q

3-ß-hydroxysteroid dehydrogenase deficiency

A
  • reduction in all steroid hormones
  • increased salt excretion
  • female-like genitalia
  • increased ACTH
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17
Q

17-a-hydroxylase deficiency

A
  • no cortisol or sex hormones
  • increased aldosterone synthesis→hypertension, hypokalemia
  • female-like genitalia
  • increased ACTH
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18
Q

21-ß-hydroxylase deficiency

A
  • most common form of CAH
  • no mineralocorticoids or glucocorticoids
  • overproduction of androgens→virilization
  • increased ACTH
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19
Q

11-ß-1 hydroxylase deficiency

A
  • no cortisol, aldosterone, or corticosteroid
  • overproduction of androgen→virilization
  • increased deoxycorticosterone→fluid retension
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20
Q

what is the mechanism of action and the effects of aldosterone?

A
  • increased blood pressure
  • angiotensinogen is cleaved by renin in liver→angiotensin I which is cleaved by ACE→angiotensin II→adrenal cortex (zona glomerulosa)→aldosterone→GPCR→IP3/DAG
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21
Q

what is the mechanism of release and action of the sex hormones?

A
  • required for sexual differentiation and reproduction
  • GrH→ant. pituitary→LH and FSH→GPCR→PKA/cAMP
  • LH: testosterone, estrogens and progesterones
  • androstenedione→testosterone→estrogens using aromatase
    • aromatase inhibitors: treatment for hormone positive breast cancer in post menopausal women
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22
Q

how do steroid hormones work?

A

diffuse through plasma membrane→nucleus and dimerizes→ligand-receptor complex bind co-activators/repressors→binds hormone response elements (HRE) in DNA→increase/decrease transcription

  • HRE is in promoter region or enhancer element to ensure coordinated regulation
  • associates with DNA via zinc finger
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23
Q

vitamin Ds

A
  • group of sterols that regulate plasma Ca2+ and phosphate in a stimularprocess as steroid hormones
  • active form is 1,25diOH-D3 (calcitrol)
    • exogenous from diet or endogenous from intermediate in cholesterol pathway, requires light
    • 1-hydroxylase is extensively regulated: low phosphate/Ca2+ increases; calcitrol decreases
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24
Q

how does vitamin D stimulate intestinal absorption of Ca2+?

A

VDR complex→nucleus and forms heterodimer with retinoid-X-receptor→binds co-activator proteins→recognizes VDRE

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25
Q

how does plasma Ca2+ moderate vitamin D levels?

A
  • low Ca2+→elevation of calcitriol and PTH→increase in Ca absorption, bone resorption, and inhibition of Ca secretion
  • high Ca2+→lower PTH→conversion from calcitriol to inactive D→elevated expression of calcitonin→inhibits bone resorption, enhances Ca excretion
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26
Q

how is ethanol detoxified in the liver?

A
  • ethanol→acetate and NADH in cytosol
    • uses ADH
  • acetaldehyde→acetate in mitochondria
    • uses ALDH2
    • acetaldahyde damages liver and other organs→flushing, nausea, vomiting, distaste for alcohol
    • ALDH inhibitors for alcoholism
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27
Q

microsomal ethanol oxidizing system (MEOS)

A
  • high blood alcohol leads to induction of MEOS
  • comprised of ER cytochrome P450 enzymes (esp. CYP2E1) which has a higher Km for ethanol than ADH
  • increases enthanol clearance from blood but produces acetaldehyde faster than ALDH can metabolize it→liver damage and ROS
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28
Q

acute effects of ethanol ingestion

A

due to elevated NADH/NAD+ ratio

  • inhibtion of FA oxidation
  • hyperlipidemia
  • ketogenesis
  • inhibition of gluconeogenesis
  • lactic acidosis
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29
Q

chronic effects of ethanol ingestion

A

due to acetaldehyde and ROS production

  • hepatic steatosis
  • hepatitis
  • fibrosis→sclerosis→cirrhosis
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30
Q

hepatic cirrhosis

A

irreversible damage to liver; initial hepatomegaly (full of fat and crossed with collagen dibers) but shinks as liver loses function

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31
Q

importance of vitamin A

A
  • visual cycle
  • deficiency: night blindness→zerophthalmia
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32
Q

importance of vitamin K

A
  • localization of enzymes required for blood clotting
  • deficiency: easy bruising, bleeding, hemorrhage
  • affects: newborns without microbes to make K and long-term antibiotic use
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33
Q

importance of vitamin E

A
  • antioxidant, protects membrane and LCL from oxidative damage
  • deficiency: CVD, neurological symptoms
  • affects: severe prolongued defects in absorption (e.g., celiac disease)
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34
Q

importance of vitamin C

A
  • cofactor for collagen formation, required for steroid synthesis in stress response, aids in iron absorption
  • deficiency: scurvy (decreased wound healing, osteoporosis, corkscrew hairs and pinpoint hemorrhages)
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35
Q

what are the energy releasing B vitamins

A
  • B1: thiamine
  • B2: riboflavin
  • B3: niacin
  • B5: pantothenic acid
  • B6: pyroxidine
  • biotin
  • deficiencies first show signs in rapidly growing tissues
36
Q

importance of thiamine B1

A

precursor for TPP (critical in nervous system)

  • wernicke-korsakoff syndrome: mental disturbance, unsteady gate, uncoordinated eye movements; common with alcoholics
  • **beriberi: **extreme muscle weakness, polyneuropathy,
  • affects: alcoholics and those on diet of polished rice
37
Q

importance of riboflavin B2

A

precursor of FAD/FMN (energy metabolism)

  • ariboflavinosis: rash around nose, perioral inflammation
38
Q

importance of niacin B3

A

precursor of NAD/NADP (energy metabolism)

  • pellagra: dermatitis, diarrhea, and dementia
  • affects: those on corn/millet baesd diet
39
Q

importance of pyroxidine B6

A

presursor of LPL (required for glycogen breakdown, GABA, and heme synthesis

  • deficiency: irritability, nervousness, depression→convulsions
  • affects TB patients treated on isoniazid, alcoholics
40
Q

what are the hematopoietic B vitamins

A
  • B9: folate
  • B12: cobalamin
  • lead to deficiency of nucleotides
41
Q

importance of folate B9

A

precursor of THF

  • deficiency: megaloblastic/macrocytic anemia
  • folate trap: bypass B12 deficiency, make side product that results in demyelination→neurological symptoms
  • affects: pregnancy women and alcoholics
42
Q

importance of cobalamin B12

A

coenzyme in methionine synthesis; can store a lot of it but must bind to intrinsic factor to be absorbed

  • pernicious anemia: lack of intrinsic facotor→megaloblastic/macrocytic anemia with demyelination
  • affects long time strict vegetarians
43
Q

importance of calcium

A

critical role in signalin, coagulation, muscle contraction, and bone

  • mild deficiency: muscle cramps, osteoporosis
  • severe deficiency: rickets, osteoporosis
44
Q

importance of magnesium

A

high levels in bones, important for enzymes using MgATP

  • deficiency: weakness tremors, arrhythmias
  • afects: patients on diuretics or with severe vomiting/diarrhea
45
Q

importance of phosphorus

A

mostly present in phosphates, major component f bone, required in all energy-producing reactions

  • deficiency is rare→rickets, muscle weakness and breakdown, seizure
46
Q

importance of iron

A

O2/CO2 transport, ox phos, cofactor in noheme Fe processes and cytochromes

  • deficiecy: microcytic/hypochromic anemia
  • long term toxicity: hemochromatosis (Fe depositis→liver and cardiac problems, can compromise mitochondrial function)
  • affects menstruating women
47
Q

importance of copper

A

assists Fe absorption, cfactor for enzymes required in collagen synthesis, FA metabolism, and elimination of ROS

  • deficiency: rare, anemia, hypercholesterolemia
  • affects individuals with menkes’ syndrome (genetic mutation of Cu transporter in golgi) or consuming excessive Zn
  • **wilson’s disease: **ATPB7 loses ability to sequester copper→copper overload→liver failure and cancer; ring around iris
48
Q

importance of zinc

A

cofactor for metalloenzymes, structural role in many proteins (Zn finger domains)

  • deficiency: poor wound healing, dermatitis, reduced taste acuity, poor growth and impaired sexual development in children
49
Q

importance of chromium

A

chromodulin facilitates insulin binding to its receptor; deficiency→impaired glucose tolerance (from reduced insulin effectiveness)

50
Q

importance of iodine

A

critical for T3/T4, regulates BMR

  • deficiency: goiter, hyper/hypothyroidism
51
Q

importance of selenium

A

antioxidant enzymes, component of deiodinase enzymes

  • deficiency: keshan disease in areas with little selenium in soil→cardiomyopathy and cretinism
52
Q

what are the 5 most important ROS?

A
  • superoxide O2-
  • hydrogen peroxide H202
  • hydroxyl radical OH
  • nitric oxide NO
  • peroxynitride ONOO-
53
Q

how are ROS generated?

A
  • 1-5% of electrons leak through complex I or II in ETC; increases with high membrane potential, high NADH/NAD ratio, ETC damage, xenobiotics, electrom backflow in complex 1
  • cellular oxidases
  • superoxide spontaneously dismutes to O2 and H2O2
54
Q

what kinds of cellular damage is caused by superoxide?

A
  • **DNA damage: mispairing, G-to-T
  • lipid damage via chain reaction: initiation (lipid radical produced after OH steal electron)→propagation (reacts with neighboring free FA)→termination (2 lipid radicas collide or react with antioxidant)
  • protein damage via direct damage and carbonylation (addition of reactive carbonyl groups)
55
Q

what kinds of cellular damage is caused by H2O2?

A

**reversible damage to thiol groups in proteins; **H202 is not a free radical but a 2 electron oxidant that reacts poorly with most biological moleculres and can oxidize cysteinyl residues to form disulfide cross-links with other cysteines

56
Q

superoxide dismutase

A

converts 2 superoxides into O2 and less toxic H2O2

57
Q

what enzymes decompose H202?

A
  • glutathione peroxidase: reduce glutathione GSH is oxidized and product is oxidized to glutatione (GSSG)
  • **peroxiredoxin pathway: **peroxiredoxin + H2O2→H2O + oxidized peroxiredoxin with disulfide bond, reduced by thioredoxin; ultimate reducing equivalent is NADPH from pentose phosphate shunt or TCA shunt
  • catalase
58
Q

what are in vivo synthesized antioxidants?

A
  • glutathione: GSH keeps sulfhydryls or cysteines of proteins reduced and maintains their biological activity
  • CoQ10 (ubiquinone): inhibits lipid peroxidation
59
Q

what are dietary antioxidants?

A
  • vitamin E: protects membrane lipids and lipoproteins
  • vitamin C: protects other molecules
  • plant phenols: cardioprotective by inhibiting LDL oxidation
  • falvonoids: reduce coronary heart diseases and stroke
60
Q

how does the regulated generation of ROS at low levels mediate physiological functions?

A
  • reqired for redox signaling, differentiation and apoptosis, cellular processes
  • ROS-mediated cellular signaling: H2O2 is a second messenger for redox signaling
61
Q

lipostat hypothesis

A

resists body weight changes by balancing food intake/expenditures; set point determined by genetic and environmental factors; can be reset leading to long-term weight gain

  • signal: adipocytes synthesize/release leptin (concentrations are generally proportional to fat accumulation in adipose tissue)
  • sensor: brain cells in particular regions express leptin receptors on their surfaces and they integrate the intensity of signal (an/orexigenic)
  • effector: hypothalamic centers inlfuence energy intake/expenditure by releasing other molecules
62
Q

leptin resistance

A

leptin→decreased feeding, increased energy expenditure, decreased body weight BUT in most obese people, leptin level is extremely high, suggesting that they become insensitive

63
Q

what are the components of energy expenditure

A
  • resting energy expenditure
  • energy expended in digesting, metabolizing, storing food
  • volitional exercise
  • nonexercise activity thermogenesis
  • adaptive (facultative) thermogenesis
64
Q

brown fat vs. white fat

A

brown fat is rich in mitochondria and express high levels of UPC1 (FA/proton symporters activated by FA, promotes reentry of protons into mitochondrial matrix→heat)

  • white fat can convert to beige by increasing exercise activity→more mitochondria and UPC1
65
Q

metabolic syndrome

A

preclinical metabolic alterations associated with obesity

66
Q

insulin resistance

A

failure of blood glucose to decline in the presence of insulin

  • obesity: adipose tissue reduces glucose uptake→hyperglycemia and global effect on tissues through release of substances that reduce sensitivity to insulin (increased leptin, decreased adiponectin, increased NEFA)
67
Q

lipotoxicity theory of insulin resistance

A

DAG accumulation due to excessive caloric intake

  • oversupply in muscle→PKC→interferes with insulin signaling and inhibits Glut4 translocaion to plasma membrane→reduces uptake of glucose from skeletal muscle
  • oversupply in liver→glycogen synthase level decreases, glucoseneogenesis increases as a consequence
68
Q

low-grade systemic inflammation theory of insulin resistance

A

resident macrophages can increase up to 50% in adipose tissue (expansion overwhelms vascular system)→hypoxia→apoptosis→release of inflammatory cytokines→inhibits insulin signaling in local adipocytes as well as in liver and muscle

69
Q

AMPK

A

important energy sensor (activated by AMP and inhibited by ATP) that promotes catabolism and inhibits ATP consuption; directly controls ß oxidation

  • can be activated by leptin, adiponectin, exercise, and metformin
70
Q

metformin

A

diabetic drug that phosphorylates/activates AMPK→phosphorylation/inhibition of ACC1 and 2→ß oxidation→prevents hepatic FA overaccumulation, improves insulin sensitivity, reduces hepatic glucose output

71
Q

what are the theories of insulin resistance in obesity?

A
  • lipotoxicity
  • low-grade systemic inflammation
  • AMPK
  • severe mitochondrial dysfunction
  • macronutrients increase ectopic lipid accumulation in liver
  • visceral fat
72
Q

what macronutrients can lead to insulin resistance?

A

fructose and alcohol are lipogenic→steattosis→insulin resistance

73
Q

how does visceral fat lead to insulin resistance?

A
  • direct drainage of adipocytes to liver
  • increased ß3 adrenergic receptors→increased lipolysis (and decreased response to insulin that inhibits lipolysis)→increased NEFA
  • increased secretion of pro-inflammatory molecules that induce insulin resistance in organs
74
Q

drug targets for obesity and metabolic syndrome

A
  • fibrates: target PPARa→lower TG, raise HDL, lower LDL
  • TZDs: target PPARy→decrease circulating NEFA→increase insulin sensitivity
75
Q

mutation accumulation theory of aging

A

force of selection is too weak to oppose accumulation of germ-line mutations with late-acting deleterious affects

  • ex. huntington’s disease: late onset allows for reproductin before dying
76
Q

antagonistic pleiotropy theory of aging

A

some genes may be selected for beneficial effects on reproductive and survival successes but also have deleterious effects with age

  • ex. bone calcification: important for fitness in young but causes calcification of arteries and myocardiac infarction in old
77
Q

disposal soma theory of aging

A

evolution acts primarily to maximize reproductive fitness and the soma is disposable after reproductive success

  • ex. nake mole rat: long lifespan vs. other rates (dwells undergroun→reduced predation→reduced pressure for reproductive success→increased resources for soma maintenance)
78
Q

free radical/oxidative stress theory of aging

A

toxic byproducts of metabolism (OH, H2O2) can damage cellular components and lead to aging

  • vicious cycle: free radicals damage mitochondria→more free radicals from ETC
79
Q

mitochondrial theory of aging

A

mitochondrial dysfunction may cause aging dependent or independent of ATP and ROS production

80
Q

cell senescence/telomere shortening theory of aging

A

end replication provlem→telomere needs to be synthesized by telomerase but most somatic cells do not have this enzyme→shortened telomeres cannot protect chromosome→double strand break-like DNA damage response→senescence

81
Q

somatic mutation theory of aging

A

age-related accumulations of mutations→genetic instability→senescence or cancer

82
Q

proteostatic stress theory of aging

A

proteins can get misfolded over time→protein dysfunction, disruption of cell membranes, formation of toxic aggregates, and apoptotic/nonapoptotic cell death

83
Q

hutchinson gilford progeria

A

LMNA gene defect→accelerated aging that is segmental (recapitulates cardiovascular aging, no neurodegeneration or cancer)

84
Q

molecular principles underpinning interventions for promoting healthspan

A
  • caloric restriction: activation of FOXO, reduced insulin→reduced mTOR signaling, activation of AMPK, increased atophagy
  • physical exercise: modest leisure time exercise→4.5 year life extension
  • rapamycin: reduces mTOR signaling→longer lifespan in mice but side effects include immunosuppression, impaired wound healing, insulin resistance, cataracts, and testicular degeneration
85
Q

how can low GH increase healthspan?

A

dwarf mice defective in GH and GHR→downregulated mTOR→cell growth slows→cells can allocate more resources for repair and maintenance

GER UNIT 8 (3 decks)

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