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
2
Q
synthesis of cholesterol
A
- in all cells except RBCs
- Actyl CoA→HMG CoA
- HMG CoA→mevalonate by cytosolic HMC CoA reductase (rate limiting step)
- mevalonate (6C) to cholesterol through series of phosphorylations via 5C, 10C, 30C intermediates
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
4
Q
statins
A
structural analogs of HMG that competitively inhibit HMG CoA reductase→lower plasma levels of cholesterol
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
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)
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
8
Q
structure of lipoproteins
A
- inner hydrophobic core of TAG and cholesterol esters
- shell of amphipathic phospholipids, includes unesterified cholesterol and apolipoproteins
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
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
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
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:
- LDL binding
- where pH dependent conformational change occurs
- 3&4. make receptor accessible for LDL
- single pass through bilayer
- associates with clathrin, initiates endocytosis when LDL is bound
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
14
Q
what is the rate limiting step in steroid hormone formation?
A
conversion of cholesterol to pregnenolone by cholesterol desmolase (located on IMM)
15
Q
congenital adrenal hyperplasias
A
deficiencies in enzymes of steroid synthesis→build up of substrates/diminished products
16
Q
3-ß-hydroxysteroid dehydrogenase deficiency
A
- reduction in all steroid hormones
- increased salt excretion
- female-like genitalia
- increased ACTH
17
Q
17-a-hydroxylase deficiency
A
- no cortisol or sex hormones
- increased aldosterone synthesis→hypertension, hypokalemia
- female-like genitalia
- increased ACTH
18
Q
21-ß-hydroxylase deficiency
A
- most common form of CAH
- no mineralocorticoids or glucocorticoids
- overproduction of androgens→virilization
- increased ACTH
19
Q
11-ß-1 hydroxylase deficiency
A
- no cortisol, aldosterone, or corticosteroid
- overproduction of androgen→virilization
- increased deoxycorticosterone→fluid retension
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
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
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
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
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
25
how does plasma Ca2+ moderate vitamin D levels?
* **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**
26
how is ethanol detoxified in the liver?
* **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*
27
microsomal ethanol oxidizing system (MEOS)
* **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
28
acute effects of ethanol ingestion
due to elevated NADH/NAD+ ratio
* inhibtion of FA oxidation
* hyperlipidemia
* ketogenesis
* inhibition of gluconeogenesis
* lactic acidosis
29
chronic effects of ethanol ingestion
due to acetaldehyde and ROS production
* hepatic steatosis
* hepatitis
* fibrosis→sclerosis→cirrhosis
30
hepatic cirrhosis
irreversible damage to liver; initial hepatomegaly (full of fat and crossed with collagen dibers) but shinks as liver loses function
31
importance of vitamin A
* visual cycle
* deficiency: night blindness→zerophthalmia
32
importance of vitamin K
* localization of enzymes required for blood clotting
* deficiency: easy bruising, bleeding, hemorrhage
* affects: newborns without microbes to make K and long-term antibiotic use
33
importance of vitamin E
* antioxidant, protects membrane and LCL from oxidative damage
* deficiency: CVD, neurological symptoms
* affects: severe prolongued defects in absorption (e.g., celiac disease)
34
importance of vitamin C
* 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)
35
what are the energy releasing B vitamins
* B1: thiamine
* B2: riboflavin
* B3: niacin
* B5: pantothenic acid
* B6: pyroxidine
* biotin
* deficiencies first show signs in rapidly growing tissues
36
importance of thiamine B1
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
importance of riboflavin B2
precursor of FAD/FMN (energy metabolism)
* **ariboflavinosis:** rash around nose, perioral inflammation
38
importance of niacin B3
precursor of NAD/NADP (energy metabolism)
* **pellagra:** dermatitis, diarrhea, and dementia
* affects: those on corn/millet baesd diet
39
importance of pyroxidine B6
presursor of LPL (required for glycogen breakdown, GABA, and heme synthesis
* deficiency: irritability, nervousness, depression→convulsions
* affects *TB patients treated on isoniazid*, alcoholics
40
what are the hematopoietic B vitamins
* B9: folate
* B12: cobalamin
* lead to deficiency of nucleotides
41
importance of folate B9
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
importance of cobalamin B12
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
importance of calcium
critical role in signalin, coagulation, muscle contraction, and bone
* mild deficiency: muscle cramps, osteoporosis
* severe deficiency: rickets, osteoporosis
44
importance of magnesium
high levels in bones, important for enzymes using MgATP
* deficiency: weakness tremors, arrhythmias
* afects: patients on diuretics or with severe vomiting/diarrhea
45
importance of phosphorus
mostly present in phosphates, major component f bone, required in all energy-producing reactions
* deficiency is rare→rickets, muscle weakness and breakdown, seizure
46
importance of iron
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
importance of copper
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
importance of zinc
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
importance of chromium
chromodulin facilitates insulin binding to its receptor; deficiency→impaired glucose tolerance (from reduced insulin effectiveness)
50
importance of iodine
critical for T3/T4, regulates BMR
* deficiency: goiter, hyper/hypothyroidism
51
importance of selenium
antioxidant enzymes, component of deiodinase enzymes
* deficiency: **keshan disease** in areas with little selenium in soil→cardiomyopathy and cretinism
52
what are the 5 most important ROS?
* superoxide O2-
* hydrogen peroxide H202
* hydroxyl radical OH
* nitric oxide NO
* peroxynitride ONOO-
53
how are ROS generated?
* **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
what kinds of cellular damage is caused by superoxide?
* **\*\*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
what kinds of cellular damage is caused by H2O2?
**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
superoxide dismutase
converts 2 superoxides into O2 and less toxic H2O2
57
what enzymes decompose H202?
* **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
what are in vivo synthesized antioxidants?
* glutathione: GSH keeps sulfhydryls or cysteines of proteins reduced and maintains their biological activity
* CoQ10 (ubiquinone): inhibits lipid peroxidation
59
what are dietary antioxidants?
* 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
how does the regulated generation of ROS at low levels mediate physiological functions?
* reqired for **redox signaling**, differentiation and **apoptosis**, cellular processes
* **ROS-mediated cellular signaling:** *H2O2 is a second messenger for redox signaling*
61
lipostat hypothesis
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
leptin resistance
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
what are the components of energy expenditure
* resting energy expenditure
* energy expended in digesting, metabolizing, storing food
* volitional exercise
* nonexercise activity thermogenesis
* adaptive (facultative) thermogenesis
64
brown fat vs. white fat
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
metabolic syndrome
preclinical metabolic alterations associated with obesity
66
insulin resistance
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
lipotoxicity theory of insulin resistance
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
low-grade systemic inflammation theory of insulin resistance
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
AMPK
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
metformin
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
what are the theories of insulin resistance in obesity?
* lipotoxicity
* low-grade systemic inflammation
* AMPK
* severe mitochondrial dysfunction
* macronutrients increase ectopic lipid accumulation in liver
* visceral fat
72
what macronutrients can lead to insulin resistance?
fructose and alcohol are lipogenic→steattosis→insulin resistance
73
how does visceral fat lead to insulin resistance?
* 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
drug targets for obesity and metabolic syndrome
* fibrates: target PPARa→lower TG, raise HDL, lower LDL
* TZDs: target PPARy→decrease circulating NEFA→increase insulin sensitivity
75
mutation accumulation theory of aging
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
antagonistic pleiotropy theory of aging
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
disposal soma theory of aging
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
free radical/oxidative stress theory of aging
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
mitochondrial theory of aging
mitochondrial dysfunction may cause aging dependent or independent of ATP and ROS production
80
cell senescence/telomere shortening theory of aging
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
somatic mutation theory of aging
age-related accumulations of mutations→genetic instability→senescence or cancer
82
proteostatic stress theory of aging
proteins can get misfolded over time→protein dysfunction, disruption of cell membranes, formation of toxic aggregates, and apoptotic/nonapoptotic cell death
83
hutchinson gilford progeria
LMNA gene defect→accelerated aging that is segmental (recapitulates cardiovascular aging, no neurodegeneration or cancer)
84
molecular principles underpinning interventions for promoting healthspan
* **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
how can low GH increase healthspan?
dwarf mice defective in GH and GHR→downregulated mTOR→cell growth slows→cells can allocate more resources for repair and maintenance
