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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