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441 Cards in this Set
- Front
- Back
eicosanoids =
|
derivatives of Arachidonic Acid
- PG's, TX's, LT's |
|
eicosanoids are potent:
|
*lipid* local messengers
- paracrine, autocrine |
|
Arachindonic Acid =
|
omega6
- w3 is an analog - both are PUFA's |
|
*there are ALWAYS 3 carbons between:*
|
double-bonds
|
|
examples of w3 =
|
EPA, DHA
|
|
***ALL w6's and w3's are:
|
essential fatty acids
(EFA's) |
|
*arachidonic acid can be made from ______________, but that itself is ______________*
|
linoleic acid;
essential |
|
w6 and w3 **compete** for
|
the enzymes that make eicosanoids
|
|
w3 is better than w6;
|
less inflammatory, more anti-inflammatory
|
|
BOTH w6 and w3 are
|
PUFA's
|
|
PUFA =
|
PolyUnsaturated FA
(MUFA = mono unsaturated) |
|
a saturated FA is tightly packed b/c of no double-bonds; therefore it's:
|
solid at RT
|
|
good sources of w3:
(3) |
1. SMASH
2. albacore tuna 3. flaxseed oil |
|
3 facts about eicosanoids:
|
1. extremely potent
2. extremely short-lived 3. found only in small amounts |
|
eicosanoids are UNlike true hormones because:
(3) |
1. they're made in **almost all tissues**
2. they aren't transported in blood (local) 3. act immediately, then destroyed - NOT stored |
|
for every effect of an eicosanoid, some other eicosanoid will have
|
the opposite effect
|
|
***what's the primary control point of eicosanoid synthesis?***
|
**PLA2**
(phospholipase A2) |
|
which enzyme is responsible for LT synthesis?
|
**lipoxygenase**
|
|
which enzymes are responsible for making the common precursor of PG's and TX's?
|
COX
|
|
***the kind of eicosanoid produced depends on:***
|
***the kind of enzymes found in a particular cell-type***
|
|
the amount of eicosanoid produced depends on:
|
the amount of ARA released
|
|
eicosanoid synthesis and action:
Signal => PLA2 => |
ARA => COX / LOX = > PG/TX/LT => outside of cell => receptor of same or nearby cell => G-alpha => 2nd messenger => cell response => physiological effect
***eicosanoids use the G-alpha pathway*** |
|
***there are _______ intracellular sites of eicosanoid synthesis***
|
many
|
|
***which drugs block PLA2 action?***
|
***anti-inflammatory steroids***
(e.g. cortisol) |
|
***what blocks LOX?***
|
***anti-asthmatics***
|
|
***what blocks COX?***
|
***NSAIDS***
|
|
aspirin =>
|
**irreversible** binding of COX
|
|
PG/TX/LT receptor ________ are also used to block eicosanoid aciton
|
antagonists
|
|
***COX1 and COX2 are found in different ratios among:***
|
different tissues
|
|
COX1 actions:
(2) |
1. protects stomach lining
2. promotes platelet aggregation (blood clots are more likely) |
|
COX2 actions:
(2) |
1. inflammatory response
2. inhibits platelet aggregation |
|
aspirin can generally inhibit both COX's, but:
|
a given cell will have more of one than the other => different effects depending on where in the body aspirin acts
|
|
aspirin can decrease inflammation by blocking COX2, but also
|
decrease stomach protection by blocking COX1, if both enzymes are found in the same tissue
|
|
solution to generability of aspirin =
|
**selective** COX2 inhibitors
|
|
2 kinds of specific COX2 inhibitors:
|
1. Celebrex
2. Vioxx |
|
COX1 =>
|
TGA2 => inc. platelet agg.
|
|
COX2 =>
|
PGI2 => dec. platelet agg.
|
|
***polarity of bile salts:***
|
bile salts are **amphipathic**
- made of both polar and nonpolar groups |
|
bile salts are made from:
where? |
cholesterol
- in the liver |
|
bile is stored in
|
the gall bladder
|
|
lactose is always coming into the liver from
|
RBC's
- used in GNG |
|
what enzyme hydrolyzes dietary fats into FA's and MG (monoglycerol)?
|
**pancreatic lipase, PL**
|
|
how long are medium-chain FA's?
|
12C+
|
|
dietary medium-chain FA's are absorbed directly into
|
the portal circulation
- NOT broken down into FA's and MG |
|
longer-chain FA's are broken down in the lumen, then:
|
converted back into TG's in the intestinal mucosa
=> chylomicrons => lymphatic system => blood => adipose for storage, muscle for energy |
|
chylomicron components =
|
TG + cholesterol + phospholipids
|
|
in the fed state, insulin is
|
high,
and Glucagon is low |
|
FA's found in VLDL have two destinations:
|
1. to adipose for storage
2. to muscle for energy (exercising muscle if fed, resting muscle if fasting) |
|
***excess glucose and AA's are converted to:***
|
**TG's in the liver and adipose**
(liver then sends its TG's to adipose via VLDL) |
|
HSL =
|
hormone-sensitive lipase
|
|
***HSL is stimulated by:***
(2) |
1. Glucagon
2. EPI |
|
***FA's released into the blood during the fasting state =>***
|
energy for everything *except* for brain and RBC's
|
|
glycerol released by TG breakdown in the fasting state =
|
very minor source for GNG
|
|
ACoA => ketone bodies during
|
starvation
|
|
***what INHIBITS HSL?***
|
**insulin**
|
|
***insulin stimulates _________ to remove FA's from ______ and store them in ___________
|
LPL;
VLDL; adipose |
|
***Remodeling = ***
|
FA's released from chylomicrons are re-esterified to TG's and exported as VLDL
check |
|
in resting muscle in the fed state, insulin stimulates:
(3) |
1. glucose uptake via GLUT 4
2. glycogen synthesis 3. protein synthesis |
|
*glycolysis is driven by:*
|
***mass action***
|
|
in the liver and adipose during stravation, Glucagon is
|
high,
while insulin is low |
|
actions of Glucagon in the starving state:
(2) |
1. *activates HSL* => FA's released from adipose
2. *inhibits* FA and TG synthesis |
|
***what drives Beta-oxidation of FA's to ACoA in liver?***
|
***mass action***
- ACoA => energy |
|
***as GNG depletes OAA, ***
|
**ACoA cannot enter Krebs**
=> increased conversion to ketone bodies (only during starvation) |
|
Glucagon effect on muscle in the fasting state:
|
**Glucagon has NO effect**
|
|
***what's the primary source of energy for muscle in the fasting state?***
|
**FA's**
|
|
in the fasting state, protein synthesis in muscle is NOT stimulated (no insulin). Net result =
|
proteolysis
=> release of AA's for GNG and for that same muscle to use |
|
***during fasting, muscle glycogen stores are:***
|
***untouched***
|
|
GLUT's 1 and 3:
(four) |
1. low Km
2. insulin-independent 3. ~ brain and RBC's 4. (GLUT 3 found in skeletal muscle) |
|
GLUT 4:
(4) |
1. low Km
2. regulated by insulin - active only in fed state** 3. **~ muscle, adipose** 4. also activated by muscle contraction |
|
GLUT 2
(3) |
1. high Km
2. active ONLY in fed state 3. ~ liver, B-islet cells |
|
Type I diabetes =
|
insulin NOT produced
|
|
no insulin => inc. HSL =>
|
FA's accumulate => mass-action => inc. ACoA => ketone bodies
|
|
****why does ACoA get converted to ketone bodies in Type I diabetes?****
|
b/c no insulin = inc. GNG => dec. OAA
=> nothing for ACoA to react with |
|
no insulin also = no
|
FA or TG synthesis
|
|
***net result of Type I:***
(2) |
1. hyperglycemia
2. ketonemia |
|
Type I in resting muscle: no insulin =
|
protein synthesis NOT stimulated => proteolysis => release of AA's
|
|
effect of Type I on glycogen:
|
*glycogen stores are NOT severely depleted*
(b/c blood glucose levels are high => GLUT 3's are active => inc. uptake of glucose |
|
Type II diabetes =
|
insulin resistance
|
|
***in Type II, there are HIGH concentrations of FA's in the blood, because:
|
body switches to them for energy
=> TG synthesis => **accumulation in the MUSCLE** |
|
DAG might cause
|
insulin resistance
|
|
***in resting muscle, long-term exposure to insulin =>
|
***up-regulation of glycolysis enzymes,
=> pyruvate accumulation => lactate production*** |
|
***inc. blood lactate =>
(2) |
1. hyperuricemia (gout)
2. dec. ketosis*** |
|
Type II => dyslipidemia:
(3) |
1. adipokines stimulate HSL in adipose => TG's in adipose => FA's in blood => mass-action => FA accumulation in liver
2. inc. TG synthesis in liver => VLDL => bloodstream 3. adipokines inhibit LPL in adipose ==> dyslipidemia (VLDL's have nowhere to go) |
|
***net result of Type II in liver:***
(2) |
1. **dyslipidemia**
2. hyperglycemia |
|
where does Beta-oxidation occur?
|
in the mit.
(FA => ACoA) |
|
**what's the source of ALL carbons in the body?**
|
**ACoA**
|
|
ACoA is made from:
|
carbs and proteins
- **NADPH and ATP are required for synthesis** |
|
***where does synthesis of FA's occur?***
|
in the **cytosol**
|
|
problem: FA synthesis occurs in the cytosol, but
|
***ACoA can't get out of the mit.,*** where it's made
|
|
ACoA is unable to cross the mit. membrane; solution =
|
citrate accumulates in mit. =>
citrate-pyruvate shuttle brings it out => citrate converted BACK to ACoA |
|
the citrate-pyruvate shuttle facts:
(2) |
1. uses NADH
- regenerates NAD+ so that glycolysis can continue 2. creates NADPH - used to reduce ACoA |
|
****what's the rate-limiting enzyme of FA synthesis?****
what is it's cofactor? |
***ACC***
- **biotin** |
|
what rxn does ACC regulate?
|
ACoA ----> malonyl-CoA
|
|
malonyl-CoA =
|
"activated intermediate"
|
|
what are the two isozymes of ACC?
|
1. ACC1
2. ACC2 |
|
****ACC1 is found in:
|
cytosol of liver and adipose
|
|
****ACC2:
(2) |
1. found on mit. membrane of muscle and liver
2. produces malonyl-CoA for inhibition of Beta-oxidation in fed state |
|
***what enzymes catalyze all the remaining rxns, after ACC?***
|
**FA Synthase**
|
|
what does FAS possess that makes it ideal for FA synthesis from ACoA?
|
***a chain very similar to ACoA***
- this is where the chemistry takes place |
|
ACoA => malonyl-CoA =>=>
|
palmitoyl CoA
|
|
palmitoyl CoA =
|
a precursor to longer FA's
- itself a FA |
|
***remodeling =****
|
other enzymes elongate and add double-bonds to FA's
=> allows body to determine FA composition of membranes |
|
example of enzyme involved in remodeling:
|
desaturase
- requires copper |
|
***why are linoleic and linolenic acid essential?***
|
***b/c we lack the enzymes necessary to introduce double-bonds into the w6 and w3 positions
- that's why we have to eat them |
|
ACC is stimulated by:
(2) |
1. citrate
2. insulin |
|
ACC is inhibited by:
|
1. palmitoyl CoA
2. Glucagon |
|
citrate and palmitoyl CoA act on ACC at the:
|
cellular level
|
|
insulina and Glucagon effect on ACC occurs at the:
|
whole-body level
|
|
fed state ~ high ______________________
|
insulin and palmitoyl CoA
(palmitoyl CoA is an end product in fed state, => inactivates ACC after a while) |
|
what other enzyme INactivates ACC?
|
AMP-PK,
via P'n |
|
***AMP-PK is active when:
|
AMP is high
- i.e. fasting, exercise |
|
***AMP-PK activity =>=>
|
dec. FA synthesis,
inc. Beta-oxidation |
|
AMP-PK is INactive when:
|
glucose is high
- i.e. fed state, type II diabetes |
|
SREBP-1c =
|
enzyme in liver
|
|
SREBP-1c is normally inactive and bound to the
|
ER
|
|
SREBP-1c is transported to the Golgi and cleaved to be activated; then it goes to
|
the nucleus => **binds to SER sequences of DNA**
|
|
SREBP-1c binding to SER of DNA =>
(3) |
***increased expression of:
1. ACC 2. FAS 3. gly-3P- acyltransferase => inc. FA synthesis |
|
****insulin increases both the levels and activation of:****
|
SREBP-1c
|
|
what else increases SREBP-1c action?
|
TNFa-like adipokines
|
|
***what inhibits SREBP-1c action?***
|
omega3's
- activate PPARa => inhibits SREBP-1c => dec. ACC, FAS, glt-3P-acyltransferase |
|
in the fed state, high insulin has the following effects on FA synthesis:
(2) |
1. inc. activity of ACC
2. inc. expression of ACC, FAS, gly3Pat => inc. FA synth. |
|
***in the fasting state, everything having to do with ACC is
|
reversed
- ACC inhibited, levels of enzyme expression are decreased |
|
***chronic high glucose => increased:***
|
ACC activity
|
|
TNFa-like adipokines increase
|
enzyme expression of ACC, FAS, gly3P-a.t.
|
|
***phospholipids can be made during both:***
|
fed AND fasting state
(see Sheet) |
|
***BOTH muscle and adipose have most of the enzymes needed for GNG => ***
|
can do *glycero*neogenesis
|
|
**phosphatidic acid =>
(2) |
1. phospholipids
2. DAG |
|
***ALL cells make phosphoilipids out of:***
|
phosphatidic acid
|
|
***glycerol-3-P-acyl-transferase is REQUIRED for:***
|
TG synthesis
|
|
***TG synthesis is stimulated in the ____ state AND by _________
|
fed state;
insulin |
|
TKR's active form =
|
***active DIMER***
|
|
IRS =
|
insulin receptor substrate
|
|
***dimerization of TKR =>
|
constitutive activity, even though NO hormone is bound***
|
|
hydrophilic hormones =>
|
signal transduction
|
|
***activating TKR's propagate the signal by:***
|
binding/activating >1 intracellular signaling protein
=> >1 signaling pathway |
|
TKR's IC segment binds recruited proteins at their
|
**SH2 or PTB domains**
=> forms a scaffold for recruiting downstream proteins ***PH domain binds it to membrane*** |
|
***a single TKR can bind to multiple, different proteins at the same time =>
|
***two pathways that synergize to produce the optimal response***
- one pathway by itself will not lead to the optimal response |
|
two standard sides of activated TKR =
|
1. Ras pathway
2. PI3K pathway |
|
constitutively active TKR's =>
|
uncontrolled cell growth
|
|
what does the drug Gleevec do?
|
***keeps Ras away from membrane***
=> stops uncontrolled cell growth |
|
***Ras is aberrant in:***
|
many cancers
|
|
no mit. =
|
NO GNG
(because no OAA) |
|
autophosphorylation ~
|
INTERchain
=> *multiple* (P-Y) residues |
|
P-Y domain of SH2 =
|
**primary binding determinant of SH2**
XXXX = discrimination site |
|
active TKR =
|
a scaffold
|
|
enzyme defects of MD's can be:
|
partial or complete
=> presentation may vary among individuals with the same disease, and within the same family |
|
glucose levels should be between:
|
80 and 100
|
|
Metabolic Disorders are NOT
|
uncommon
- affect all ages |
|
MD's in newborns:
(4) |
1. normal delivery
2. but poor feeding/vomiting/progressive coma 3. often misdiagnosed as pneumonia 4. ***fatal if undiagnosed/untreated*** |
|
MD's in adults:
(2) |
1. milder symptoms
2. fasting/illness/exercise may precipitate the disease |
|
***most MD's are _____ in inheritance***
|
AR
|
|
***clinical symptoms of MD's are similar to those of:***
(2) |
1. infeciton
2. intoxication |
|
**need to order SPECIAL blood and urine tests to determine:
|
whether Metabolic Disorder is in play
- samples are best collected during *acute* episodes |
|
MD's are treatable, especially if
|
diagnosed early
|
|
MD's affect ALL:
|
races and ethnicities
|
|
when to suspect MD in children:
(8) |
1. **unexplained disease, esp. after normal pregnancy
2. metabolic acidosis and/or hypoglycemia 3. liver dysfunction 4. unexplained myopathy 5. signs of storage disease 6. unusual odors 7. failure to thrive or developmental delay 8. food aversion |
|
suspect MD if Family History shows:
(5) |
1. **consanguity** (because most of them are AR)
2. sibling w/ unexplained illness or death as neonate 3. sibling with developmental delay, mental retardation, autism 4. mother with MD 5. unexplained fetal loss |
|
precipitating factors of MD:
(4) |
1. **increased protein intake**
2. fasting 3. illness **(inc. protein breakdown)** 4. exercise |
|
too much NH3 =>
|
brain edema => death
|
|
NH3 above ____ in neonates = trouble
|
150
|
|
OTC = ornithine transcarbamylase deficiency:
(3) |
1. urea cycle disorder
2. X-linked 3. females with OTC may be asymptomatic |
|
ALL urea cycle disorders except for OTC are:
|
AR
|
|
childhood symptoms of MD:
(10) |
1. fatigue/lethargy
2. feeding difficulties 3. vomiting 4. tachypnia 5. progressive coma 6. **behavior changes** 7. myopathy 8. jerks/seizures 9. jaundice 10. odors |
|
prompt treatment of MD prevents
|
neurological damage
|
|
one type of MD = Organic Acidemias:
(6) |
1. AR diseases
2. defect in BCAA catabolism 3. **acidosis** 4. hypoglycemia 5. elevated NH3 6. abnormal liver function |
|
disorders with reduced fasting tolerance:
(3) |
1. glycogen storage disorders
2. FA oxidation disorders 3. disorders of ketogenesis |
|
low HCO3 ~
|
acidosis
|
|
normal NH3 levels =
|
0 to 35
|
|
tips for MD:
(6) |
1. suspect MD often
2. get a detailed FH 3. ask about food illnesses, fasting, and other precipitating factors 4. **a normal test result does NOT rule out MD** 5. prescribe a decreased protein intake 6. ***measure ammonia*** |
|
mit. are dynamic, provide
|
energy
|
|
***mit. are involved in:***
|
**apoptosis**
|
|
mit. are associated with many
|
diseases
|
|
**outer membrane of the mit. :
(4) |
1. **permeable**
2. contains porins 3. ions and mlcls <10 kDa can get through 4. larger mlcls require active transport via membrane transport proteins |
|
**inner membrane of the mit.
(2) |
1. ***impermeable***
2. holds ETC, ATPase, and various transport proteins |
|
***what makes the inner mitochondrial membrane impermeable?
|
***lots of cardiolipin***
|
|
mit. matrix contains:
(3) |
1. hundreds of enzymes
2. mit. DNA 3. ribosomes, tRNA |
|
***where are H's pumped into?***
|
into the Intermembrane Space of the mit.
- out of the matrix |
|
how do you get ATP out of the mit. matrix where it's produced?
|
**ANT**
- Ad. Nucleotide Translocase |
|
how do you get NAD+ out of the mit. matrix?
|
**malate-aspartate shuttle**
|
|
cyanide inhibits
|
complex 4 of ETC
|
|
oligomycin blocks
|
ATP Synthase
|
|
***mit. uncouplers allow:***
|
protons to get back into the matrix from the IMS *without* ATPase
- thereby dissipating the proton gradient, without ATP production |
|
ATPase's can work in:
|
**reverse**
- actually move H's back out into IMS = signal that mit.'s doing fine |
|
how efficient is Oxidative Phosphorylation?
|
55%
- rest is heat |
|
uncoupling ATPase's => dec. efficiency =>
|
more heat produced
- a natural thing to do in some cases |
|
UCP1 ~
|
brown fat cells in newborn mammals, hibernating animals
|
|
UCP2 is **ubiquitous**, ~
|
weight regulation
|
|
UCP 4, 5 are exclusive to
|
mammalian brain tissue and testis
- may dec. ROS |
|
***mit. are constantly undergoing:***
|
fission and fusion
|
|
2 reasons for fission:
|
1. since mit. MOVE through cells, smaller = faster
2. mitophagy - sequester the damaged part, fission it out |
|
4 facets of mit. DNA:
|
1. circular
2. NO histones 3. **different codons from the nuclear genome** 4. **high rate of mutations** |
|
LHON, MELAS =
|
mit. diseases
|
|
Warburg effect =
|
how cancer cells do NOT get their ATP from mit.
- but use glycolysis rather than ATP - b/c you need lipids and NT's for OxP |
|
the body views Type I as:
|
the fasting state, b/c insulin is not around
|
|
in the fasting state, FA's provide energy for:
|
all tissues EXCEPT brain and RBC's
|
|
***what's the key enzyme of Beta-Ox?***
|
**HSL**
|
|
**how are FA's transported through the blood?**
|
bound to albumin
|
|
***where does B-Ox occur?***
|
in the mit.
- FA's must be transported in |
|
****what's the rate-limiting enzyme of FA transport into mit.?****
|
CPT-1
|
|
regarding transport of FA's, exercise increases levels of:
(3) |
CPT-1, translocase, and CPT-2
|
|
FA synthesis occurs in
|
the cytosol
|
|
B-Ox =
|
the chemical reversal of FA synthesis
|
|
***how is B-ox not exactly a reversal of FA synthesis?***
(3) |
1. uses different enzymes
2. occurs in mit, rather than cytosol 3. produces FADH2, NADH |
|
peroxisomes = organelles that cleave FA's down to:
|
octanoyl-CoA and ACoA
|
|
peroxisomes are MOST efficient when they work with:
|
***long-chain FA's***
|
|
citrate spilling over into cytosol =
|
too much citrate in the mitochondria
|
|
other pathways apart from Beta-Ox exist for degrading:
|
odd-chain, branched-chain, and unsaturated FA's
|
|
Beta-Oxidation in the fed state:
|
turned off
**ACC 1 and ACC2 are activated by insulin** - so FA synthesis is going on, and malonyl-CoA is increased |
|
ACC2 increases
|
malonyl-CoA
|
|
***malonyl-CoA inhibits:
|
***CPT-1
=> *no Beta-Ox* |
|
Beta-Ox during the fasting state:
|
dec activity of ACC's, inc. activity of HSL
=> FA's to liver => B-Ox |
|
***what does PPARa do?***
|
***increases Beta-Ox *enzyme* levels, esp. CPT-1***
(also inhibits SREBP) |
|
what do w3's and fibrate drugs do?
|
***activate PPARa***
|
|
***when is PPARa active?***
(2) |
Fasting and Exercise
|
|
***what do insulin and glucose do to PPARa?***
|
*inhibit* it
=> inc. FA synthesis - occurs in Fed state |
|
what does PCG-1a do?
|
*stimualtes mit. biogenesis*
=> more mit. |
|
regular exercise => inc. in
|
PCG-1a => more mit.
|
|
Beta-Ox in Type 2 diabetes: high insulin =>
|
inhibited PPARa => dec. Beta-Ox
|
|
***interventions that will improve Beta-Oxidation with Type II diabetes:***
(3) |
1. eat w3's
2. use fibrate drugs 3. exercise - ***doubles PPARa in muscle cells*** |
|
what two things increase Beta-Oxidaiton while dec. FA synthesis?
|
1. w3's
2. fibrates |
|
***where is the only place that ketones are found?***
|
in the **liver mit.**
|
|
acetone
|
smells
~ ketones |
|
majority of GNG substrates =
|
skeletal muscle protein breakdown
|
|
which two enzymes are highest in the liver mit. and thus allow the liver mit. to produce ketones?
|
***HMG CoA synthase and HMG CoA lyase***
|
|
***which enzyme is necessary to convert ketone bodies to energy?***
|
**CoA Transferase**
|
|
which is the only tissue that can't use ketones for energy, and why not?
|
***the liver***,
because it doesn't have CoA Transferase |
|
***what initiates ketogenesis?***
|
real (fasting, Type 1) or perceived (Type 2) inc. in Glucagon-to-insulin ratio
|
|
inc. in Glucagon-to-Insulin ratio => HSL activated => mass action toward B-Oxidation => ACoA accumulates in mit. Meanwhile,
(2) |
1. excess NADH and ATP inhibits use of ACoA
2. no ACC activity = ACoA can't be used => shunted to ketogenic pathway |
|
**when is ketone formation primed?**
|
when ACoA production *exceeds* utilization
- meanwhile, OAA stores are depleted by GNG (-> a requirement for ketogenesis) |
|
Ketogenesis and Type 2:
|
does NOT occur, because lactate from muscle is converted to OAA
=> ***no ketogenesis in Type 2*** |
|
Beta-Oxidation disorders ~ dysfunctional transports, =>
|
FA's can't come into mit. to be oxidized for energy => cells use more and more glucose => **hypoglycemia**
|
|
B-Oxidation **enzyme** deficiencies do NOT result in:
|
ketone bodies,
b/c no ACoA is made |
|
the insulin receptor =
|
***a Class II TKR***
that uses BOTH Ras and PI3K |
|
Ca2+ coming into pancreatic B-cells =>
|
insulin secretion from vesicles into bloodstream
- ***inc. in ATP shuts down Ca2+ channels*** |
|
AKT =
|
PKB
|
|
P'n of insulin receptor =>
|
IRS 1 or 2 recruited => P'd
=> SH2 of recruited adaptor binds to P-Tyr's |
|
***Insulin, when bound, affects BOTH:
|
expression (via transcription)
and activity of proteins (via dephospohorylation - sometimes activates, sometimes inactivates) |
|
***insulin has different effects in:
|
the liver, muscle, adipose
|
|
Insulin's affect on Liver:
(5) |
1. dec. GNG
2. inhibit glycogenolysis 3. inc. glycolysis 4. inc. FA synthesis 5. inc. glycogen synthesis |
|
Insulin's affect on Muscle:
(4) |
1. inhibits glycogenolysis
2. inc. glucose uptake 3. inc. glycogenesis 4. inc. protein synthesis (via expression of translation proteins) |
|
which tissues are GLUT 4's found in?
|
muscle and adipose
|
|
Type II is a _______ disease:
|
polygenic;
there's no one gene |
|
how does Type II occur?
(4) |
1. obesity/fatty liver
2. target cells become insulin-resistant 3. pancreatic cells temporarily compensate by inc. insulin production - syndrome X occurs 4. they eventually poop out => insulin prod. falls |
|
obesity is contributive to Type II, NOT:
|
causative
|
|
why Type II occurs - theories:
(2 with target cells, 2 with pancreatic B-cells) (4) |
1. impaired insulin receptor funciton
2. impaired insulin control of GLUT 4's 3. impaired synthesis or secretion of insulin 4. impaired B-cell neogenesis, survival, and proliferation |
|
in diabetes, MANY problems occur at
|
the same time
- not just one problem |
|
TNFa =
|
an inflammatory cytokine
|
|
***in adipose tissue, what 2 factors contribute to insulin resistance?***
|
TNFa and FFA's
- TNFa P's Ser rather than Tyr of IRS - FFA's P'late Ser and competitively inhibit GLUT 4's |
|
Phosphorylating Ser rather than Tyr =>
|
**impaired** signal of insulin pathway
=> opposite of all insulin effects |
|
which IRS do pancreatic B-cells require for neogenesis, survival, and proliferatoin?
|
IRS2
|
|
target cells have both IRS1 and IRS2; loss of one =>
|
compensation by the other
- not so with B-cells - loss of IRS2 = bad |
|
what does high [glucose] impair?
|
***B-cell survival***
- glucose inhibits GLP receptor => dec. B-cell survival and dec. insulin secretion |
|
treatment for Type I =
|
insulin
- b/c autoimmune loss of B-cells = no insulin produced |
|
Type II is highly correlated with
|
obesity
- but not all obese people have it or will have it |
|
remember that diabetes ~ lots of
|
urine
|
|
BMI levels:
|
normal = 20-24.9
overweight = 25-29.9 obese = 30+ |
|
genetic component of Type II is strong, but
|
environment and epigenetics also have significant influence
|
|
normal glucose level =
|
64 to 126 mg/dL
|
|
untreated diabetes => LOTS of
|
complications
- eyes, kidney, heart, etc. |
|
oral glucose test =
|
take 75g of glucose, measure every half hour for 2 hours
|
|
**insulin resistance => an increase in:
|
GNG
- b/c insulin isn't inhibiting it |
|
even in diabetics, glucose eventually leaves the blood as
|
the kidney is clearing it
|
|
insulin resistance => inc. FA's into blood =>
|
liver takes them up => becomes more fatty => **produces more lipoproteins** => dyslipidemia
|
|
two possible mechanisms of insulin resistance:
|
1. abnormal P'n of Ser prevents activation of target proteins
and/or 2. inadequate activating P'n of PKB both occur with obesity and inc. in TG's in muscle and liver |
|
T2D progression:
(4) |
1. starts with obesity or fatty liver
2. tissue becomes insulin-resistant 3. initially, pancreas compensates - blood glucose levels are near normal - but Metabolic Syndrome can begin 4. eventually pancreas loses the ability to produce sufficient insulin (called Decompensation) - happens for many reasons |
|
2 potential mechanisms for tissue becoming insulin-resistant:
|
A. adipose tissue and associated macrophages secrete adipokines and FA's
B. liver and muscle TG stores increase |
|
A. adipose tissue and associated macrophages secrete adipokines and FA's, while adiponectin secretion decreases =>
|
TNFa and FA's => Ser, inhibit GLUT's
decreased adiponectin => AMP-PK not activated => dec. B-Ox, inc. TG |
|
B. liver and muscle TG stores increase =>
|
abnormal P'n of signal pathway
|
|
diabetes is sometimes correctable with lifestyle and drug therapy:
(4) |
1. inc. AMP-PK => inc. B-Ox
2. bariatric surgery 3. inc. PPaRa 4. exercise calls up GLUT 4's in skeletal muscle, without need of insulin => inc. glucose tolerance |
|
when can Type II be **reversed**?
|
in cases where the pancreas retains the ability to produce normal insulin levels
|
|
if the pancreas has given out, Type II is NOT
|
reversible
- can only be managed with insulin |
|
Metabolic Syndrome = 3+ of the following criteria:
(5) |
1. waist >40 in men, >35 in women (not Asians)
2. TG's >150 mg/dL 3. low HDL 4. HTN 5. fasting plasma glucose 100+ mg/dL |
|
**most people with Syndrome X are:**
|
insulin-resistant
|
|
***Metabolic Syndrome increases risk for:***
(2) |
1. Type II
2. CVD |
|
AGE =
(a condition of diabetes) |
Advanced Glycation End product
- inc. glucose in blood can glom onto proteins => dysfunction of those proteins => kidney disease, retinopathy (e.g. glycosylated Hb) |
|
4 types of tissue:
|
1. epithelial
2. connective 3. muscle 4. nerve |
|
epithelial tissue:
(2) |
1. liver, kidney, skin
2. cells are high, ECM is low |
|
connective tissue:
(2) |
1. bone, cartilage
2. few cells, LOTS of ECM |
|
both muscle and nerve tissue are surrounded by
|
basement membrane
|
|
basal lamina =
|
basement membrane
|
|
microvilli =>
|
inc. SA for more absorption
|
|
apical surface ~
|
intestinal lumen
|
|
zonula occludens =
|
TJ's
|
|
zonula adherins =
|
AJ's
|
|
macula adherins =
|
desmosomes
|
|
glycocalyx =
|
carb-rich **coating** prominent on microvilli of intestinal cells
|
|
what's the function of glycocalyx?
|
protection
|
|
TJ's:
(3) |
1. prevent passage of fluid and mlcls
2. linked to actin filaments 3. *claudin* and *occludin* are responsible for the barrier |
|
which TJ protein links to actin filaments?
|
occludin
|
|
AJ's:
|
major actin links, cadherins
|
|
desmosomes:
(2) |
1. strong attachment
2. ~ adhesion of IF's (keratin in epithelial cells) |
|
which proteins mediate adhesion in desmosomes?
**what class of adhering proteins are they?** |
desmoglein and desmocollin
- **both are cadherins** |
|
keratins ~ mechanical strength; prevent epithelia from
|
tearing apart
- connect to hemidesmones at the basement membrane |
|
keratin = an
|
intermediate filament
|
|
hemidesmosomes:
(2) |
1. link basal surface of epithelial cells to the basement membrane
2. anchor IF's 3. integrins |
|
what's the CAM of hemidesmosomes?
|
**integrin**
|
|
2 diseases of Desmo and Hemidesmosomes:
|
1. Pemphigus
2. Pemphigoid *** |
|
pemphigus =
(3) |
1. autoimmune
2. affects Desmosomes 3. **antibodies against desmogleins** |
|
pemphigoid =
(2) |
1. autoimmune
2. antibodies against hemidesmosome proteins |
|
***diseases of Desmo and Hemidesmosomes => disruption of adhesion =>
|
blistering => blister breaks => bacterial infection
|
|
**in many invasive cancers, there's a loss of:**
|
E-cadherin expression
=> dec. cell-cell adhesion |
|
what is a Junctional Complex?
|
TJ + AJ + Des
- ***ALL epithelial cells have a JC, in that order*** |
|
focal adhesions to ECM use
|
integrins
- seen in culture, rarely in epithelia |
|
Gap Junction ~
|
communication between cells
- characteristic tramline appearance |
|
gap junctions allow passage of mlcls <
|
1500 Da
- ions - found in heart |
|
***gap junctions consist of:***
|
an array of connexons,
themselves made up of connexins |
|
***what shuts down connexons?***
|
***Ca2+***
|
|
CAM's =
|
cell adhesion mlcls
|
|
4 kinds of CAM's:
|
1. cadherins
2. integrins 3. Ig superfamily 4. selectins |
|
cadherins:
(4) |
1. homophilic - only connect to other cadherins
2. Ca2+-dependent 3. Beta subunit links to membrane 4. alpha subunit links to actin via catenin |
|
integrins:
(5) |
1. heterophilic
2. aB dimers 3. divalent cation-dependent 4. prominent receptors for ECM 5. usually link to actin; with hemidesmosomes, link to keratin |
|
Ig superfamily:
(2) |
1. do NOT require divalent cation
2. homo OR heterophilic (e.g. N-CAM) |
|
selectins:
(4) |
1. heterophilic
2. bind carbs to cell 3. Ca2+-dependent 4. first adhesion cells involved in inflammation |
|
10^9 number of cell divisions = number of divisions necessary:
|
per DAY to keep you going
|
|
***2 critical regulatory steps in the cell cycle:***
|
1. beginning of S phase
2. segregation of chromosomes in mitosis |
|
G-zero is between:
|
M and G1
- can last years - metabolically active but NOT in the cell cycle |
|
G1 ~ large increase in
|
cell size
|
|
S ~
|
DNA replication/ chromosome duplication
|
|
in the S phase, cells are highly sensitive to
|
DNA damage
|
|
prophase ~
|
chromosome condensation and envelope breakdown
|
|
prometaphase ~
|
spindle assembly and chromosomal segregation
|
|
cytokinesis is NOT a part of
|
telophase
|
|
committed step of mitosis =
|
segregation of chromosomes
|
|
confluent =
|
out of room
|
|
"transformed" cell =
|
cancer cell
|
|
immortal cells =
|
intermediates between normal and transformed cells
|
|
cells are normally anchored, except for
|
RBC's, WBC's, etc.
|
|
unlimited proliferation of cells is a result of:
|
re-expressing telomerase
=> unstable genome |
|
**true test of whether it's a cancer =
|
**whether or not it produces tumors in mice**
|
|
3 sources of genome instability:
|
1. chromosome replication errors
2. DNA repair defects 3. chromosome segregation errors |
|
MPF absolutely necessary to:
|
initiate mitosis
|
|
MPF =
|
Cyclin B/Cdk1
- ***a Ser/Thr kinase*** |
|
Cdk1 levels don't change during the cell cycle, but
|
cyclin DOES
|
|
one thing that MPF P's =
|
lamin A
=> disassembly => nuc. envelope breakdown |
|
Mitotic Index =
|
number of cells undergoing mitosis
|
|
mitosis is SHORT, so tumor cells have a
LOW: |
mitotic index
|
|
Cyclin-Cdk's govern:
|
cell cycle transitions
|
|
substrates need both Cdk and Cyclin:
|
P'n site is at Cdk,
binding site is on cyclin |
|
2 key points about cell cycle regulation:
|
1. Cdk's govern transitions
2. Cyclins are ESSENTIAL for Cdk activity |
|
cell in G-zero must NOT re-enter cycle unless:
|
a proper mitogenic signal is received
|
|
***cyclin-D gene is a:***
|
proto-oncogene
|
|
cyclin D is overproduced in many cancer cells => cyclin-D gene now =
|
**oncogene**
|
|
alpha-hyrdoxy group ~
|
BELOW the plane of the ring
|
|
**what's the carbon backbone of ALL steroid hormones?**
|
*cholesterol*
|
|
CYP450 =
|
heme/Fe enzyme => catalyzes hormone synthesis
|
|
**most enzymes in the synthesis of cholesterol =
|
CYP 450's
|
|
what turns CE into free cholesterol?
|
esterase
- free cholesterol then enters the mit. matrix |
|
steroid synthesis is NOT
|
constitutive
|
|
****specific hormones act on specific cell types that use:
|
specific enzymes to create specific steroid hormones
- via GCPR's |
|
***the only class of steroids that doesn't use G-alpha-S =
|
mineral corticosteroids
- ***also the only kind that ~ Renin-Angiotensin system*** |
|
progesterone =
|
an estrogen
|
|
female gonadal steroids: 3 cell types but only one branch of synthesis ~
|
all use the SAME enzymes
=> collaboration between theca and granulosa cells |
|
***what are the 2 kinds of hormonal cascades that control steroid synthesis?***
|
1. hypothalamic-pituitary cascade
2. renin-angiotensin cascade |
|
**what's the carbon backbone of ALL steroid hormones?**
|
*cholesterol*
|
|
CYP450 =
|
heme/Fe enzyme => catalyzes hormone synthesis
|
|
**most enzymes in the synthesis of cholesterol =
|
CYP 450's
|
|
what turns esterified chol. into free cholesterol?
|
lipase
- free cholesterol then enters the mit. matrix |
|
steroid synthesis is NOT
|
constitutive
|
|
****specific hormones act on specific cell types that use:
|
specific enzymes to create specific steroid hormones
- via GCPR's |
|
***the only class of steroids that doesn't use G-alpha-S =
|
mineral corticosteroids
- ***also the only kind that ~ Renin-Angiotensin system*** |
|
progesterone =
|
adrenal
|
|
female gonadal steroids: 3 cell types but only one branch of synthesis ~
|
all use the SAME enzymes
=> collaboration between theca and granulosa cells |
|
***what are the 2 kinds of hormonal cascades that control steroid synthesis?***
|
1. hypothalamic-pituitary cascade
2. renin-angiotensin cascade |
|
ACTH => G-a-S =>
(3) |
1. adrenal uptake of lipoproteins from plasma
2. conversion of CE to free cholesterol (via esterase) 3. uptake of cholesterol into mit. matrix (via Star) => inc. cortisol and DHEA production |
|
POMC = precursor of:
|
ACTH
|
|
ABC1 increases
|
efflux of cholesterol out of macrophages and into HDL => excreted via liver
|
|
Vit E decreases ROS, but does NOT
|
decrease risk of CVD
|
|
Oxidized LDL increases with
|
inc. LDL in circulation for a long time
|
|
rupture of plaque =>
|
embolism (block)
|
|
cholesterol:
(2) |
1. insoluble in water (esterified even more so)
2. bound to lipoproteins in plasma |
|
Roles of cholesterol:
(4) |
1. signal transduction
2. component of membranes and myelin - makes membrane more firm 3. precursor of bile, steroids, and Vit. D. 4. essential for embryo formation (defects are lethal) |
|
every cell can generate cholesterol, but the liver produces
|
80% of total cholesterol
|
|
***what's the control point/rls of cholesterol synthesis?***
|
HMG CoA Reductase
|
|
HMG CoA Reductase acts in the
|
cytosol
|
|
***insulin activates HMG CoA Redc, in the:
|
fed state
|
|
SCAP =
|
chaperone
|
|
***free cholesterol inhibits _____________________***
|
HMG CoA Reductase
|
|
***statins =
|
structural antagonists of HMG CoA Reductase
=> block chol. production |
|
what do statins do?
|
dec. cholesterol production
=> liver gets chol from blood for membranes, precursors, etc. |
|
***free cholesterol down-regulates:
|
LDL receptors
|
|
focus of cholesterol is the cholesterol concentration of
|
the cells,
NOT the blood |
|
***bile = the ONLY way to
|
**get rid of cholesterol**
|
|
bile = end product of
|
cholesterol catabolism in the liver
|
|
4 facets of bile acids:
|
1. necessary to solubilize cholesterol
2. excess cholesterol => gall stones 3. ***ic cholesterol in liver stimulates bile formation*** 4. **bile acids inhibit bile acids** |
|
bile =
|
50% bile acids, 50% cholesterol
|
|
***what is the rls for conversion of cholesterol to bile?***
|
7-alpha-hydroxylase
|
|
what is the main bile acid?
|
cholic acid
|
|
function of bile acids =
(3) |
1. **absolutely essential for fat digestion**
2. inc. absorption of all fats and ADEK 3. prevent gallstones |
|
***liver reabsorbs 99% of bile acids*** (same for cholesterol)
- ***remaining 1% = |
vehicle for elimination of **cholesterol**
|
|
enterohepatic circulation =
|
bile leaves liver => circulation => comes back to liver
|
|
**bile acids are stored in the
|
gall bladder
- released into the intestine when we eat |
|
LDL => clathrin-coated pits =>
|
lysosomes => free cholesterol => **conversion to bile acids or storage**
|
|
**cholesterol inhibits:
|
LDL receptors
|
|
3 reasons why American diet is bad:
|
1. high cholesterol => dec. LDL receptors => inc. LDL in blood
2. sat. fat => inhibition of ACAT => dec. storage => inc. chol. (also dec. LDL receptors) 3. low fiber => bile NOT excreted => inhibits 7alpha-hydroxylase => chol. builds up => dec. LDL receptors => inc. LDL in circulation |
|
ACAT uses PUFA's to
|
increase storage of cholesterol
|
|
**where are lipids synthesized in the cell?**
|
on the Smooth ER
|
|
Smooth ER:
(2) |
1. no ribosomes
2. ~ detox |
|
flippases translocate proteins that are destined for
|
the outer leaflet of the membrane
|
|
***what do free ribosomes synthesize?***
(5) |
1. soluble cytoplasmic proteins
2. peripheral membrane proteins 3. INTRAnuclear proteins 4. mit. proteins 5. peroxisomal proteins |
|
ER sequesters and holds:
|
Ca2+
|
|
nucleolus = site of:
|
rRNA synthesis
|
|
***SRP binds protein being translated =>
(3) |
1. translation stops
2. SRP receptor on ER calls SRP 3. translation continues with the new protein running into the ER lumen |
|
3 kinds of protein modifications in the ER:
|
1. glycosylation
2. disulfide bonds 3. correct folding via chaperones |
|
e.g. of ER modification: Asn-linked oligosaccharide is added from the high energy lipid,
|
dolichol;
=> calnexin and calretculin (chaperones) fold the glycosylated protein => sugars are trimmed, chap's release |
|
**incorrectly-folded proteins are
|
degraded
|
|
correctly-folded proteins =>
|
Golgi, via vesicles
|
|
2 types of vesicle coats:
|
1. clathrin
2. COP I |
|
clathrin coats ~ vesicles from
|
plasma membrane or Golgi
|
|
COP I ~
|
vesicles from the ER to Golgi
|
|
|
|
|
SNARES help with:
|
fusion of vesicles to target membrane
|
|
KDEL =
|
ER retention signal for proteins
|
|
secretion in vesicles can be either
|
constitutive or regulated
|
|
in epithelial cells, proteins are selectively sorted for
|
apical or basolateral membranes
|
|
***all lysosomes contain:***
|
hydrolases, operating at pH 5
|
|
***what signal targets proteins to lysosomes?***
|
**mannose-6- P
|
|
lysosomal storage disease =>
|
accumulation of undigested components, as hydrolases aren't working
|
|
peroxisomes =
|
degradative organelles
|
|
proteins destined for the nuclear matrix have an:
|
NLS
|
|
endocytosis is unique to
|
euk's
|
|
4 types of endocytosis:
|
1. pinocytosis
2. potocytosis 3. phagocytosis 4. RME |
|
some pinocytosis is
|
receptor-mediated
|
|
potocytosis:
(4) |
1. invaginations called caveolae
2. contain GPI-anchored proteins and signaling mlcls 3. ***major structural protein = caveolin***, a cholesterol-binding protein 4. responsible for transcytosis |
|
transcytosis =
|
transport from apical to basolateral membrane
e.g. mother's AB's to newborn |
|
phagocytosis:
(3) |
1. ingestion of large particles via specific receptors
- like bacteria, old or damaged cells 2. primarily in macrophages 3. phagosomes then fuse with lysosomes or Golgi vesicles containing lysosomal hydrolases |
|
"zipper mechanism" ~
|
engulfing AB-coated bacteria
|
|
RME:
(3) |
1. specific receptors concentrated on coated pits
2. uptake of GF's and nutrients at low external concentrations 3. coated pits become coated vesicles in cytosol |
|
triskelion anatomy of vesicles ~
|
clathrin-coated vesicles
|
|
uncoating of clathrin-coated pit is triggered by:
|
Hsc70, a chaperone
=> triskelions |
|
primary lysosomes are new and have no components inside; =>
|
uniform stain
|
|
2 kinds of secondary lysosomes:
|
1. autophage/cytosomes
2. phagolysosomes |
|
autophage/cytosomes ~
|
eating up organelles
|
|
phagolysosomes ~
|
phagocytes
|
|
LDL is taken up by
|
**RME**
|
|
defective LDL receptors =>
|
hypercholesteremia (in the blood)
|
|
homozygous for hypercholesteremia =
|
NO LDL receptors
=> heart attacks at early age |
|
heterozygous for hypercholesteremia =
|
fewer LDL receptors
|
|
statins dec. cholesterol production => =>
|
cholesterol taken from blood for membrane, precursor synthesis
|
|
many toxins and parasites use
|
endocytosis to get into cells
- includes RME |
|
viruses will fuse with endosome membranes, allowing their
|
infectious nucleic acid into the cytoplasm
- use RME |
|
HIV enters the cell via
|
fusion of its lipid membrane with the plasma membrane
|