Study your flashcards anywhere!

Download the official Cram app for free >

  • Shuffle
    Toggle On
    Toggle Off
  • Alphabetize
    Toggle On
    Toggle Off
  • Front First
    Toggle On
    Toggle Off
  • Both Sides
    Toggle On
    Toggle Off
  • Read
    Toggle On
    Toggle Off

How to study your flashcards.

Right/Left arrow keys: Navigate between flashcards.right arrow keyleft arrow key

Up/Down arrow keys: Flip the card between the front and back.down keyup key

H key: Show hint (3rd side).h key

A key: Read text to speech.a key


Play button


Play button




Click to flip

344 Cards in this Set

  • Front
  • Back
caloric density of carbs?
avg 4.1kcal/g, but varies
caloric denisty of ethanol?
7.1kcal/g -so drinkers have high cal, low nutrient diet
caloric density of fat?
avg 9.3kcal/g, TGs-> Fas + glycerol. Fas have high caloric value, glycerol little (it's like carbs)
caloric density of protein?
avg 4.1kcal/g. Not completely combusted due to leftover urea. Each AA has different caloric value
3 major components of enegy expenditure?
BMR, physical activity, adaptive thermogenesis (change BMR in adipose and skeletal muscle
what's thermogenesis?
making heat at rest, resembles BMR at rest
what's BMR?
caloric consumption in resting, awake, post-absorptive state. It mean no muscular activity. It is the energy required to perform basic cell and organ functions
how does sleep affect BMR?
drop 10%
how does starvation affect BMR?
drop 40% (counterproductive in dieting)
how does age affect BMR?
decreases 10% from age 20-60
how does gender affect BMR?
slightly higher in males
how does thyroid hormone affect BMR?
(↑TH→ ↑BMR). Hypothyroidism -> obese. Hyperthyroid->thin
constancy/variability in TH?
relatively constant in most people, changes seasonally
how does surface area relate to BMR?
inverse due to greater heat loss in smaller animals (e.g. mouse BMR is 10x greater than horse)
relative role of physical activity in energy expenditure?
biggest determinant
how many times more energy does brisk walking require than BMR?
4-5 times
cycling, dancing?
6-7 times
characterisitics of insulin receptor?
tetrameric, part of RTK (receptor tyrosine kinase), 2 extracellular alpha subunits disulfide bonded to 2 membrane-spanning beta subunits
what happens to receptor upon insulin binding?
autophosphorylation of intracellular beta subunits, then activates other subunits via phosphorylation
activated insulin receptor activity in skeletal muscle and adipose?
translocate glut4 to surface (in these tissues only, not in liver).
what happens when insulin removed?
glut4 goes back into vesicles (implications in insulin resistance)
how does insulin affect mitosis?
mitogenic, like all RTKs, via SH2 and SH3 domains
how does insulin signaling stop?
insulin and receptors are internalized into vesicles.
what two things can happen after termination?
retroendocytosis (vesicles re-fuse with membrane, releasing insulin), or degradation of insulin.
three steps to insulin degradation?
1)vesicles acidified, cause insulin to fall off, 2)vesicles separate into receptor vesicles and insulin vesicles, 3)insulin degrades, and receptors with reused or degraded
how does glucagon signal?
via a specific glucagon GPCR.
how do GPCRs work?
ligand binds, GTP displaces GDP, alpha subunit activates adelylyl cyclase, converts ATP to cAMP, activates PKA
what do beta and gamma subunits do?
stay behind, recruit GRK-2 (G-receptor kinase), which phosphorylates GPCR, which recruits beta-arrestin, which associates with clatherin to internalize GPCR and activates MAP kinase
how do insulin and glucagon interact?
do exactly opposite things. Glucagon promotes catabolism, and inhibits anabolism. Insulin promotes anabolism and inhibits catabolism
what four specific processes do insulin and glucagon regulate?
ketogenesis from FA oxidation, glucogenesis from proteins, glycogenolysis, lipolysis
how is energy from food divied up?
40% lost to heat, then equally divided among cell maintenance, muscle work, internal work (also given off as heat)
how are carbs absorbed?
broken down to small saccharides by amylase. Disaccharidases on brush border cleave sugars to make monosaccharides. Lactase decreases with age.
what approach to diabetes treatment takes advantage of the above mechanism?
drugs can block amylase activity, so don't absorb carbs as much, and reduce glucose spike
how are proteins absorbed?
broken down into smaller peptides
how fats absorbed?
lipase in gut breaks TGs to glycerol, FAs, and monoglycerides. Bile helps FAs and monoglycerides get absorbed, but glycerol needs to help. TGs then resynthesized in epithelial cells, packaged in chylomicrons, and sent to periphery for absorption.
how does 100g of glucose get distributed among body tissues?
liver 60%, brain 15%, muscle 15%, fat 5%, other 5%, but it's not all metabolized by these tissues
what portion of glucose gets metabolized (used) by what tissues?
brain 70% (an obligate glucose consumer, and why hypoglycemia is so critical), muscle 20%, heart 10%, kidney 2%, and very little for rest of body
how is insulin taken up and used by muscle?
insulin stimulates glut4 transport, and breakdown by hexokinase.
how does insulin affect glycogen synthesis and breakdown?
promotes synthesis, inhibits breakdown.
what about glucokinase?
only in tissues that use glut2. Hexokinase only in tissues with glut4.
what regulates FA uptake by muscle?
amount in blood. It's insulin-independent
what regulates protein uptake by muscle?
insulin-dependent AA uptake
glucose uptake by fat?
insulin-dependent, and converted to FA and glycerol
FA uptake by fat?
70% of FA uptake is from lipoproteins using LPL
how is fat in adipocytes released?
hormone-sensitive lipase (HSL) is upregulated by glucagon and inhibited by insulin
2 ways to bring glucose to liver?
1) direct (40%), via glut2, followed by glucokinase (GK), and stored as glycogen. And 2) indirect (60%), derived from pyruvate and lactate (which are metabolites of glucose from other tissues), metabolized into glycogen. (only occurs for first 2 hours after meal ingested)
3 main effects of insulin on the liver?
1)protein, TG, glycogen synthesis, 2)AA uptake, 3)inhibits glucose-6-phosphatase to prevent glycogen breakdown
overall picture of what happens during fed state?
storage of protein, TG, glycogen. Oxidative phosphorylation by liver and muscle
what happens during 24 hr fast? To brain? Glycogen stores? Adipocytes? Muscle protein?
brain continues to consume glucose (obligate). glycogen in muscles and liver used first. adipocyte FA oxidation to provide energy for gluconeogenesis in liver. FAs in muscle breakdown to give energy to muscles. Muscle proteins breakdown, and taken up by liver for gluconeogenesis
importance of the corey cycle?
glycogen stores used up in 1 day, but brain still needs glucose.
how does it work?
lactate and pyruvate from glycolysis in blood cells, travels back to liver, where it is resynthesized into glucose for the brain to use. The energy to do this comes from FA oxidation
how much energy is stored in a person as glycogen?
900 calories (liver and muscle)
how much energy stored in protein?
24,000 calories
how much energy is stored in fat?
141,000 calories
how long can that last us?
about a month, if water and electrolytes are available
what changes occur after 24 hours of fasting?
gluconeogensis decreases due to lack of substrate (protein)
physiological changes to long fast?
brain starts using ketones (synthesized in liver from FFAs), prevents protein wasting and gluconeogenesis. Other major change is TH and symp tone drops, so less energy expenditure. Gluconeogenesis still continues a little as muscle breaks down less and less.
does brain work as well on ketones as on glucose?
not sure, but maybe subtle differences
why don't we become hypoglycemic when exercising (use up blood glucose)?
exercise upregulates glut4 in muscle INDEPENDENT of insulin, then liver replaces blood glucose by gluconeogenesis, which is stimulated to occur in two ways.
what two ways does gluconeogenesis increase during exercise?
1)lactate from muscles, and 2) increase in circulating NE and EPI (the MAIN WAY)
what effects on insulin and glucagon do circulating NE and EPI have?
stimulates glycogen breakdown, inhibits insulin production (to counter its inhibition on glucagon), and glucagon promotes gluconeogenesis
caloric density of carbs?
avg 4.1kcal/g, but varies
caloric denisty of ethanol?
7.1kcal/g -so drinkers have high cal, low nutrient diet
caloric density of fat?
avg 9.3kcal/g, TGs-> Fas + glycerol. Fas have high caloric value, glycerol little (it's like carbs)
caloric density of protein?
avg 4.1kcal/g. Not completely combusted due to leftover urea. Each AA has different caloric value
3 major components of enegy expenditure?
BMR, physical activity, adaptive thermogenesis (change BMR in adipose and skeletal muscle
what's thermogenesis?
making heat at rest, resembles BMR at rest
what's BMR?
caloric consumption in resting, awake, post-absorptive state. It mean no muscular activity. It is the energy required to perform basic cell and organ functions
how does sleep affect BMR?
drop 10%
how does starvation affect BMR?
drop 40% (counterproductive in dieting)
how does age affect BMR?
decreases 10% from age 20-60
how does gender affect BMR?
slightly higher in males
how does thyroid hormone affect BMR?
(↑TH→ ↑BMR). Hypothyroidism -> obese. Hyperthyroid->thin
constancy/variability in TH?
relatively constant in most people, changes seasonally
how does surface area relate to BMR?
inverse due to greater heat loss in smaller animals (e.g. mouse BMR is 10x greater than horse)
relative role of physical activity in energy expenditure?
biggest determinant
how many times more energy does brisk walking require than BMR?
4-5 times
cycling, dancing?
6-7 times
soccer, running, etc?
8-12 times
what's adaptive thermogenesis?
change in heat production in response to temp change or caloric intake
adaptive thermogeneis in response to cold? Change in O2 consumption?
shivering increases heat production. In small animals, this can increase oxygen consumption by 2-4 times (humans 5-10%)
how are BMR and adaptive thermogenesis related?
BMR is under normal conditions, but adaptive thermogenesis does modulate BMR, so they are inter-related
how does acute feeding affect BMR?
increase 25-40%
How does low protein diet affect energy storage?
decreases ability to store energy
how does cold temp affect energy balance? (acute)
increases sympathetic outflow, stimulates lipolysis, and UCP-1
increased UCP-1 transcription, mitochondria synthesis, brown fat hyperplasia, recruitment of brown fat in white fat deposits
mechanism for adaptive thermogenesis?
use ATP to shiver, and ion leak to increase Na/K ATPase
what does UCP-1 do?
uncouples oxidative phosphorylation, so more protons move into mitochondria, where they make electron transport chain more efficient, so burn more calories (and make more NADH, FADH2)
within what range of environmental tempuratures, do humans have relatively constant body temp?
between 55 and 115F. But above and below this, core body temp changes a lot
how does ovulation affect body temp?
slightly increase after ovulation
what regions of body need tightest control of temp?
brain and viscera
relationship between core body temp and rectal and oral temps?
close to each other
what part of body produces most heat during BMR?
brain and heart
how does time of day affect body temp?
slightly lower in the morning
4 mechanisms of heat transduction?
evaporation, conduction, convection, radiation
what method(s) of heat transfer is/are used for cooling off?
only evaporation. Works even in absence of sweating. Doesn't work if humid.
physiology of sweat production?
sympathetic nerves make it happen. There is low activity at rest. Most of fluid in ducts gets reabsorbed. But, when hot, blood flow increases, increasing fluid at glands and limiting reabsorption. Can sweat between 1 and 3 L per hour, depending on how well adapted
how much can clothing reduce heat loss?
about 50%
how does sympathetic system reduce heat loss in cold environment?
constricting skin blood vessels. Below 75F, already maximally constricted
at what temp are skin blood vessels maximally dilated?
location of 2 major temp sensors?
anterior hypothalamus, periphery
how are the sensors different?
ant. Hypo responds to hot and cold by inceasing firing, and measures temp of brain. But periphery sensors sense environmental temp, and mostly respond only to cold (a little sensitive to hot).
5 responses to cold?
vasoconstriction, shivering, behavioral changes, increase TH (over time), piloerection
3 responses to hot?
vasodiliation (withdraw symp tone), sweating, decrease heat generation
how does set point work?
determined by hypothalamus. Cooling mechanisms and heat generating mechanisms adjust according to body temp.
what raises the set point? How?
fever, via IL-1beta, which activates synthesis of PGs
how do NSAIDS reduce fever?
inhibit PG synthesis, so reduces set point
Pancreatic Islet are what percent of the pancreas?
What are the three islet cell types of the pancreas and what do they secrete?
Alpha cells-secrete glucagons, Beta cells-secrete insulin, Delta cells-secrete somatostatin
Where are these cells located in the “mini portal” system?
Beta-middle, alpha, outer edge, D- mixed at border between alpha and beta
When the blood flows through the islets of langerhans, what order does it pass through the cells?
Capillaries, Beta cells, maybe delta (fewer), alpha, then enters vein
What is the consequence of this order of blood flow?
insulin immediately acts on alpha cells, but glucagon has to go through entire circulation before acting on beta cells
What are the 4 breakthroughs that insulin has been the prototype protein for?
First isolated protein, First sequenced gene, First cloned gene, First recombinant protein used therapeutically
Insulin gene has
3 exons and 2 introns
The insulin protein’s alpha and beta chains are connected by three _____.
Disulfide bonds
When Pro-insulin is cleaved to mature insulin, what is cleaved away?
C peptide
What are the proportions of Insulin and C peptide in the mature vesicle?
Insulin is highly conserved especially the ______, residues that make the _______ bonds.
Cysteine residues, disulfide
How many amino acids different are bovine and porcine insulin from human?
Bovine=3, porcine=1
What is the variable part of the pro-insulin protein?
C peptide
Cleavage of C peptide at highly specific sites is done by ______ only expressed in _____.
Proteases, beta cells
What is the first form in insulin before proinsulin?
What are the molecular weights of Insulin, proinsulin, and preproinsulin?
6000kda, 9000kda, and 11000kda
What are the steps in the classical ER pathway?
1.     Ribosome begins making protein and a signal recognition protein (SRP) binds to protein and brings to ER
2.     Signal sequence receptor (SSR) brings partially synthesized protein attached to ribosome into ER and ribosome continues to synthesize rest of preproinsulin protein from the outside of the ER
3.     Signal peptidase cleaves signal peptide of protein and is released into ER
4.     Proinsulin is properly folded in the ER
5.     Secreted to Golgi in vesicles where proteases cleave C-peptide
How long does it take to make new insulin and get it ready to secrete?
2 hours
Where does insulin released during a meal come from?
In Type II diabetes, insulin storage and release are ______ for the needs of the body.
Since insulin is difficult to measure directly, how do you measure it?
Measure C-peptide, which is not metabolized by liver and issecreted in the kidneys
What was the first company to make recombinant human insulin?
What discovery made it possible to make properly folded recombinant human insulin?
You need to make proinsulin rather than mixing alpha and beta chains.
How do you remember how glucagons is synthesized?
Remember it is very similar to insulin
Describe the structure of the glucagons molecule.
Single chain, 29 a.a., 3500kda
What percent of circulating glucagons is active?
What are the other forms of inactive glucagons?
Preproglucagon, proglucagon, little biological activity
What is the consequence of differential protease expression?
Different cells express different protease which causes selective cleavage. Once gene product can become many different protein products.
Preproglucagon is made if what two cell types?
Alpha cells of pancreas and L-cells of GI tract
What is the protein product produced by L-cells?
What does GLP I do?
Augments/ increases insulin secretion, acts on brain (sold as a drug to treat diabetics)
Where is GLP I degraded?
In the blood
Insulin secretion is subject to what 2 portal systems?
Intra-islet and hepatic
How much of the secreted insulin is removed by the liver?
50% first pass
What is the therapeutic dilemma with subQ administration of insulin?
1. Liver gets too little insulin and needs more
2. Systemic gets too much if give the portal vein [insulin]
How does the insulin get to its site of action (tissue) from vascular network?
Crosses the endothelial cells of vascular by transcytosis
What is the difference between the rate of change of insulin concentration in the vascular and interstitial spaces?
Interstium is much slower
What are the proportions of insulin decrease from pancreas to tissue?
50% lost in liver, of the remaining 50%, 40% of that is does not make it to interstitial space. So, only 30% of originally secreted insulin makes it to tissues.
What is the major regulator of insulin secretion and what is the feedback?
Glucose via negative feedback
What is the first phase of the biphasic insulin secretion?
High quick spike when stored insulin is released
What stimulates this first phase?
glucose, amino acids, sulfonylureas, glucagons, and GI hormones
What is the second phase?
slower rising, less dramatic amount of insulin, new insulin is made and released
What stimulates the second phase?
Only glucose
Of the total daily insulin secreted, what percent is basal?
What percent of daily glucose exposure is basal?
During meals _____ and _____ spike together.
Glucose, insulin
How does glucose get into the beta cell to stimulate insulin secretion?
Facilitated transport through Glut2
What enzyme is called the glucose sensor and what does it do?
Glucose kinase (GK), phosphorylates glucose on side of mitochondria
What is the consequence of excess glucose present in the beta cell?
ATP levels rise so ATP:ADP ratio rises
What happens when the ATP:ADP ratio rises?
causes depolarization of cell allowing calcium to enter cell
What is the effect of the calcium influx?
Exocytosis of secretory granules of insulin
What is the job of cAMP?
potentiates the process so anything that increases cAMP levels also increases insulin secretion (only if glucose present in first place)
When is the onset of GK-Mody disease?
During youth
What causes it?
GK mutation
Heterozygotes for GK _____.
Show decreased insulin secretion
What does this disease tell us about how the body senses glucose levels?
Glucose metabolism is how we sense glucose levels, not the actual present amount of glucose
What do different meal components do to insulin levels?
a.a., carbs, and fats all increase insulin levels, a.a. almost to the level associated with glucose feeding.
Why do glucose levels rise during protein feeding?
During the cephalic phase of digestion, what causes insulin to be secreted? How do we know?
Anticipation, incretins (GLP I) and neurological stimulation. Insulin levels are greater when glucose is given orally more insulin is secreted than glucose is given IV
What are the effects of the PANS on insulin secretion?
Parasympathetic tone stimulates basal insulin secretion
Stimulation of SANS alpha receptors _____ insulin secretion while stimulation of beta receptors ______ secretion.
Blocks, stimulates
What does isoproterenol do to insulin secretion?
Why does an increase in SANS tone decrease insulin secretion?
b/c alpha receptors dominate
Why is glucagons called counter-regulatory?
almost everything that inhibits insulin secretion promotes glucagons secretion and vice versa
What are the two major regulators of glucagons secretion?
Glucose-negative feedback -à High glucose = low glucagon
Insulin-negative feedback à alpha cells immediately see insulin secretion b/c of the intra-hepatic blood flow so glucagon secretion is immediately inhibited
What is the one exception to everything of opposite for insulin and glucagon secretion?
Amino acids stimulate both insulin AND glucagons secretion
Why is this exception important?
glucagon promotes glucose synthesis while insulin promotes glucose breakdown so the overall glucose level is constant
in a protein only diet, if only insulin was secreted then the person would become hypoglycemic b/c basal glucose levels would fall without glucagons to balance it.
Somatostatin is a single chain, ____ a.a. peptide with one ______ bond.
14, disulfide
____% of somatistatin is made in delta cells of pancreas while ____% is made in the gut
25%, 75%
What is the main job of somatistatin?
To inhibit the secretion of everything.
DM is leading cause of what three conditions?
adult blindness, renal failure, amputations. (also 2-4x more CVD)
% diabetics type I, II?
5% type I, 95% type II
two classifications of type I DM?
primary (autoimmune destruction). Secondary (physical destruction)
relative role of genetics is type I DM?
monozygotic twins 50% chance. So big environmental too
what HLAs are associated with type I DM?
DR3, DR4 haplotypes. DR2 appears protective. But none of these are absolutely required.
risk of type I to general pop?
risk to parents of affected child?
risk to offspring?
8% father, 3% mother. Don't know why difference
risk to sibling?
risk to HLA identical sibling?
risk to sibling with no HLA identity?
evidences for virus-induced type I?
insulinitis (inflammation of pancreas), epidemiological clusters occur, viral titers in some type Is, animals can get type I if infected, in-vitro beta cells can be killed by certain viruses
what is only proven viral cause of type I?
congenital rubella gives 20% chance of infant getting type I
evidences for immunologic cause of type I?
insulinitis, associated with other autoimmune diseases, prevalence of anti-islet cell Abs (ICAb). High ICAb when diagnosed and falls after years pass.
possible chain of events for developing type I?
HLA linked genes, islet cell susceptibility, viral interaction with islet cells, immune response -> ICAb, beta cell failure, hyper alpha fxn
when do sxs manifest (in life of disease)
after 80-90% of beta cells gone, and often after traumatic event
is better to treat before sxs show up?
if therapy exists, and is very very safe, and if screening is very sensitive (especially with DM I being very rare)
% of DM pts that are obese?
four classes of DM type II?
regular DM, gestational (always comes back later), MODY (mature onset DM of the young), impaired glucose tolerance.
what is MODY?
mature onset of diabetes in the young. 20-30yo, otherwise healthy. Due to mutation in glucogenesis pathway (such as glucokinase)
what is IGT?
impaired glucose tolerance. It's prediabetic. Pts usually become obese, then get IGT, then DM. Each year, 7% of IGT pts get DM
procedure for OGTT?
oral glucose tolerance test. Fast 14-18 hrs, measure glucose, then feed known amount of glucose, and measure over 3 hrs.
normal glucose levels (fasting, OGTT 30-90 minutes, and OGTT 120min)?
fasting <126. OGTT 30-90 minutes <200, OGTT 120 minutes <140. Must be all of these to be normal
what glucose is diagnostic of DM?
symptoms **AND*** (fasting >126, **OR** OGTT-2hr >200)
4 organs contributing to hyperglycemia in DM?
liver (increased glucogenesis, due to insulin resistance, hyperglucagonemia, corey cycle, more FA use), muscle (main culprit in DM, less uptake of glucose), pancreas (high insulin or burned out pancreas and little insulin), adipose (similar to muscle)
how does a real meal and OGTT differ in insulin and glucose response in DM?
in mild DM, other molecules stimulate insulin production, so glucose stays under control. In severe DM, insulin cannot be made
first step to developing DM?
insulin resistance due to aging, obesity, physical inactivity
how does body respond to initial insulin resistance?
produce more insulin. It occurs in IGT, metabolic syndrome or syndrome X
two ways to have beta cell failure?
apoptosis, or stop making insulin
after beta cell failure, what happens?
glucose diposal rates decrease dramatically (but can improve with adequate control), increased hepatic glucose output, and decreased insulin secretion
evidence that insulin resistance is first step in disease process?
non-diabetic children of diabetics with high insulin sensitivity (Si-insulin) much less likely to develop DM later in life
factors that contribute to having insulin resistance?
genetics, obesity, aging, some meds, rare disorders
4 conditions resulting from insulin resistance? (even in absence of DM)
HTN, dyslipidemia, atherosclerosis, PCOS (poly cystic ovarian syndrome)
diagnosis for syndrome X (metabolic syndrome)? Has 3 of what 5 risk factors?
1. Obesity (men>40in, women>35in)
2. TGs>150
3. Low HDL (men<40, women<50)
4. BP>130/85
5. Fasting glucose >110
three endocrine mediators adipose secretes?
adipokines, cytokines, chemokines
what's adiponectin?
an adipokine (only secreted by adipose), which promotes insulin sensitivity
what's resistin?
an adipokine that promotes insulin resistance
what other adipokine is there?
what cytokines do adiipocytes secrete?
TBFa, IL6, IL1beta, and inflammatory ones
role of chemokines secreted by adipocytes?
attract macrophages by chemical gradient, hay clusters of macrophages in fat
what happens physiologically and chemically to adipose tissue as fat accumulates?
adipocytes get bigger and more numerous. Adiponectin decreases, resistin increases. This is reversible in early DM via exercise and weight loss
how does inflammation iccur from insulin resistance?
free FAs (which increase during insulin resistance due to cells "starving" of glucose) activate inflammatory pathway. Pathway is advantageous during regular fasting, so conserve glucose.
how does inflammation occur due to obesity?
fat has high number of macrophages, which produce inflammatory cytokines (more fat->more inflammation)
what is basal glucose uptake?
Rd (rate of disposal). 70% of this is non-insulin mediated uptake (NIMGU), of which the brain is most responsible
what is IMGU?
insulin-mediated glucose uptake. This is 30% of Rd
how does hyperglycemia occur during fasting?
all from glucogenesis (overproduction)
how does hyperglycemia occur after a meal?
insulin resistance, glucose from food, IMGU doesn't upregulate enough, as it does in normal persons
how does NIMGU and IMGU change during feeding?
in normal persons, IMGU becomes much larger than NIMGU
what two things to control iin order to treat hyperglycemia?
overproduction and insulin resistance need to be treated.
postprandial or fasting hyperglycemia more dangerous?
possible causes of insulin resistance?
(mutated insulin gene, incomplete conversion of proinsulin to insulin), (antagonists like hormones, Abs, FFAs), receptor or pathway defects
in type II DM, glucose transport defective in which part of the process?
translocation of glut4 to membrane decreased due to inflammation
4 different types of assaults on CV system due to hyperinsulinemia and insulin resistance?
hyperlipidemia, hyperglycemia, HTN, hypercoag/inflammation
step therapy for DM with FBG<140?
1) diet/exercise, 2)monotherapy with metformin or sulfonylurea, or others if criteria are met. 3)combo metformin + sulfonylurea 4) triple oral therapy, add insulin, refer to endocrinologist, 5)insulin-dependent
how does beta cell fxn and insulin resistance change over course of disease?
beta cell fxn declines over life of disease, but insulin resistance stops getting worse around the time of diagnosis
disadvantages of insulin therapy?
more insulin resistance, more CV risk, weight gain, hypoglycemia
what role does basal insulin play?
is 50% of all-day insulin, prevents glucose overproduction
characteristics of bolus insulin?
occurs after meal, peaks in 1 hr, 10-20% of daily insulin after each meal
onset, peak, duration of endogenous insulin?
30-60 min, 2-4 hrs, 6-10hrs
lispro, aspart?
15-30 min, 1-2hrs, 4-6 hrs
1-2hr, 4-6hr, 10-20hr
1-2hr, no peak, 24hrs
what is BIDS?
bedtime insulin + daytime sulfonylurea (to decrease nightime hepatic glucose production, decrease glucose toxicity on beta cells which increases beta cell response to sulfonylurea, and only 1 shot with limited side effects.
what insulin is used in BIDS?
70/30 or 75/25 right before dinner (long/short)
what's exenatide?
GLP-1 analog
what's pramlintide?
amylin analog (also secreted from beta cells to slow gastric emptying, antiglucagon, suppress appetite, for type I and II. Hypoglycemia is side effect
morning hyperglycemia?
can occur as gradual rise, immediate rise, or level through night, then rise
general dosing considerations for insulin?
half basal, half bolus. Need 1/2 units/kg/day divided into 3 injections per day. Adjust short-acting to carbs in meal
types of diabetic complications?
microvascular, macrovasular, GO, derm, rheumatologic, emotional
what are the microvascular complications?
retinopathy, nephropathy, neuropathy (60-70% of diabetics)
causes of microvascular complications?
basement membrane thickening, endothelium death, pericyte death
results of DCCT and Kimamoto studies on DM tx?
intensive treatment reduced HbA1c to 7% (instead of 9), much less retinopathy and nephropathy
main determinant of development and progression of microvascular complications?
severity and duration of glucose control
how to manage retinopathy?
screen, prevent, treat (eye exams annually for type II, q 5 yrs for type I, eye photographs, and control of glucose and BP. Photocoagulation-laser therapy, ACEIs
how to manage nephropathy?
yearly 24hr urine collection for microalbuminemia, and freq BP measurement
what are the types of neuropathy?
general (hand and glove), sensory (can't feel stuff on feet), motor (foot mangled)
4 elements of foot exam?
pedal pulse, inspection, vibration (128Hz), monofilament
top causes of death in diabetics?
ischemic heart disease, other heart disease, and stroke
how does CV disease occur in DM?
hyperglycemia, high FFAs, insulin resistance, all results in vasoconstriction, inflammation, thrombosis (atherogenesis)
3 non-reversible risk factors for CHD?
aging, male, genetic
7 reversible risk factors?
dyslipidemia, HTN, obesity, hyperglycemia, hyperinsulinemia, smoking, EtOH
how to reduce CV risk?
glycemic control, BP control (ACEIs), dyslipidemia control, ASA, no smoking
ASA therapy?
recommended for diabetics >30yo and at least one risk factor
derm complications?
dry skin from less sweating due to neuropathy, fungus infections, yeast infections, acanthosis nigricans, necrobiosis lipoidica (immunologic, tx w/ steroids), eruptive xanthomas
rheumatologic complications?
stiff hands (prayer sign), trigger finger, carpel tunnel, adhesive capsulitis, charcots joint.
GI complications?
gastroparesis, bacteria overgrowth, constipation, diarrhea
emotional complications?
stress, depression, poor social support, paralyzing beliefs, discouraging results, unclear plan, DM taking control of them
function od ApoA-I?
cofactor for LCAT (lecithin XOL acetyltransferase)
two disorders that lead primarily to combined hyperlipidemia?
dysbetalipoproteinemia, familial combined hyperlipidemia (FCHL)
three disorders that mainly to hypertriglyceridemia?
LPL deficiency, ApoC-II deficiency (which are both hyperchylomicronemias) familial hypertriglyceridemia
three condtions that lead to low HDL?
familial ApoA-1 deficiency, familial LCAT deficiency, Tangier disease
cause, lipids, manifestations of dysbetalipoproteinemia?
homozygosity for ApoE2, which has low affinity for hepatic receptors, so decreases clearance of ApoE-containing lipoproteins. Manifestation requires homozygosity PLUS a cofactor like DM, obesity, pregnancy, hypothyroidism, or any inceased chylomicron production or VLDL. Lipids are high chylomicrons and TG. Pts get premature atherosclerosis, CHD, palmar xanthomas, tuberous/tuberoeruptive xanthomas on elbows and knees (virtually diagnostic). Picture?
cause, lipids, manifestations of familial hyperTGemia?
unknown genetic defect (maybe high TG synthesis, low VLDL lipolysis), high TG (mostly VLDL), or high VLDL and chylomicrons. No unique signs, but usually start in adulthood, whereas LPL or ApoC-II deficiency signs start in childhood, and can rule out FCHL because FHTG shows normal LDL
four potential outcomes of plaque rupture?
partial removal of thrombogenic core (occlusion of rupture site, and healing as a complicated lesion, 2) sudden stenosis from massive bleeding into lesion 3) occlusion of lumen by thrombus (partial or complete), 4) propagation thrombus gives rise to embolus downstream
CETP cause, lipids, and manifestations?
genetic CETP deficiency. CETP usually exchanges XOL esters of HDL against TG ot other lipoproteins, so if deficient, it reduces HDL catabolism. HDL is >150, no early atherosclerosis, but no pretective effect either because low hepatic clearance.
what are the borderline range values for TC and LDL?
TC 200-239, LDL 130-159. obviously above and below these values is high and normal respectively.
four conditions that lead primarily to hypercholesterolemia?
familial hyperXOLemia (FH), familial defective ApoB (FDB), polygenic HyperXOLemia, familial CETP deficiency, and secondary hyperXOLemias
elevates Lp(a)?
not usually measured in plasma. if high, correlates with atherosclerosis. it is basically an LDL particle with ApoB, to which apo(a) is atached by S-S bond. Cause of elevation unknown. SImilar to plasminogen
how does enzyme HL work? what does it do to VLDL remnants and HDL?
hepatic lipase. attaches to heparin sulfate on hepatocytes. converts VLDL remnants to LDL, and may help HDL uptake into liver
what is XOL metabolism and reverse XOL transport?
XOL metabolism if liver and peripheral cells, reverse means from peripheral cells to liver. (LCAT is enzyme for this)
function of Apo(a)?
unknown function, but associated with high CHD, is homologous to plasminogen, may compete with plasminogen
FCHL cause, lipids, manifestations?
dominant inherited, unstable lipoprotein phenotype, maybe make too much VLDL. TG is high if VLDL overproduction occurs, but if not, then high LDL. High incidence of CHD, often with type II DM, syndrome X
what is in the core and membrane of liporproteins?
core has TGs, esterified XOL, antioxidants. Membrane has phopholipids, unesterified XOL, apolipoproteins
four roles of apolipoproteins?
req'd for assembly of lipoprotein particles, give stability to particle, determine recognition by receptors, can help as cofactors for enzymes in lipoprotein metabolism
main consequences of thrombus or embolus formation secondary to atherosclerosis?
ischemic stroke, CHD (angina, MI), peripheral vascular disease (legs), intermittent claudication (gangrene)
main function of ApoB-100?
uptake of LDL (but also VLDL, IDL).
main function of Apob-48?
on chylomicrons. made from same gene as ApoB-100, but gets truncated in intestinal cells that edits the RNA (inserts stop codon). That way, it's not recognized by LDL receptor
how to image atherosclerosis?
angiography deceiving because shows only lumen, so use doppler, B-mode ultrasonography, IV ultrasound, NMR, ultra-fast computer tomography. what lab tests measure level of atherosclerosis? % surface area (Sudan stain), cross-section of lesion, intimal/medial ration, XOL content of artery, uptake of radio-labeled antibodies in arterial wall
FDB? cause, lipids, manifestations?
familial defective ApoB, mutation in receptor binding domain of ApoB-100, so reduced binding to LDL receptors. lipoproteins and manifestation like FH (high LDL, normal chylomicrons, mild reduced HDL, premature atherosclerosis, CHD, xanthomas, is only other disorder besides FH to have NB tendon xanthomas. QUESTION. what is pop frequency, and profile of LDL particles? 1:700, and individuals still have normal LDL, just some is defective
most MIs and non-hemmhoragic stroke caused by what?
rupture of lipid-rich plaque with thrombi. What region of the lesion do most plaques rupture? 2/3 in shoulder region, where pro-inflammatory cytokines (TNFa, and ILs and metalloproteinases (secreted by macrophages) mechanically weaken the fibrous cap. the ramainder ruptures occur at top of lesion. Core lipids have high thromboplastin (tissue factor), so are highly thrombotic
what are the dangerous effects of hyperTGemia?
life-threatening pancreatitis. How much can treatment of hyperXOLemia reduce MI incidence? 5 year 30-40% reduction
what are lipoprotein phenotypes?
they are combinations of types of lipoproteins over others, and characteristics of plasma and arteries. what are the basic types, and distinguishing characteristics? 6 types: type I) high chylomicrons only. type V) high chylomicrons and VLDL. type III) high chylomicrons and VLDL remnants. (notes on these... high chylomicrons-->lactescent plasma. chylomicrons don't penetrate arterial wall, and aren't atherogenic unless VLDL remnants are high as in type III. main complication for I and V is pancreatitis). Type IV) high VLDL only, with high CHD. Type IIa, IIb) have high LDL alone or high LDL and VLDL, which both are highly atherogenic
what is LCAT, where made, what does it do?
glycoprotein made in liver, req'd for reverse XOL transport (by freeing up acceptor sites for free XOL on HDL particles. It also catalyzes the transfer of FAs from sn-2 position of lecithin to free XOL. What cofactor is req'd, and what happens if LCAT deficient? ApoA-1 req'd. familial deficiency results in high ratio of free to esterified XOL, hyperlipidemia, premature CHD, kidney disease, corneal opacities.
what changes in the vessel wall are associated with early and late lesion?
advanced lesions usually don't penetrate elastic lamina, only intimal thickening, and can sometimes cause eneurysms. early lesions are covered by intact endothelium, and a little luminal narrowing. which plaques have highest propensity to rupture? atheroma and lipid-rich pre-atheroma, even though have limited stenosis. Fibrous and calcified plaques are more stable, but cause more chronic conditions (angina, and have more stenosis)
what is major effect of familial ApoA-1 deficiency?
Low LDL (along with familial LCAT deficiency and Tangier disease). what is the cause, and manifestations? autosomal recessive mutation of ApoA-1, leads to atherosclerosis, planar xanthomas, and corneal apacities
order of density between classes of lipoproteins?
least dense: chylomicrons, VLDL, IDL, LDL, HDL, Lp(a) most dense. What are some patterns of expression of apolipoproteins on the different lipoproteins? B-48 only on chylomicrons, CI, CII, CIII always together (and found on chylomicrons, VLDL, HDL), B-100 found on all but chylomicrons and HDL. E found on all but LDL, Lp(a). HDL has A-I, A-II, A-IV. A-IV also found on chylomicrons
what is major effect of Tangier disease?
low LDL (along with familial LCAT deficiency and familial ApoA-1 deficiency). cause and manifestations? caused by autosomal codominant mutation of ABC-A1 transporter (used for XOL efflux), manifested by high XOL in tonsils (large,orange tonsils), and other lymphoid tissues, as well as Schwann cells (neuropathy), and macrophages. less atherosclerosis than expected because low TC
what is major effect of familial LCAT deficiency?
low LDL (along with familial ApoA-1 deficieny and Tangier disease). what are causes and manifestations? caused by dysfunctional LCAT (essential for reverse XOL transport by esterifying free XOL accepted by HDL, so as XOL ester is transferred into core, particle accepts additional XOL). surprisingly, no increase in atherosclerosis and CHD, but can cause corneal apacities, kidney disease, proteinuria, anemia
Where's ApoA-IV found?
HDL, chylomicrons (unknown function). Where's ApoB-48 found? chylomicrons (helps chylomicron synthesis and secretion)
Where's ApoB-100 found?
VLDL, IDL, LDL, Lp(a) (helps with VLDL synthesis, secretion, and is ligand for LDL receptor). Where's ApoC-I found? chylomicrons, VLDL, HDL
Where's ApoC-II found?
chylomicrons, VLDL, HDL (cofactor for LPL). Where is ApoC-III found? chylomicrons, VLDL, HDL. (inhibits lipoprotein binding to receptors)
function of ApoC-II?
obligatory cofactor for LPL, which is expressed on endothelial surface and activated by ApoC-II on chylomicrons, VLDL, HDL. What does LPL do next? cleave TGs in core of particle, TGs taken up into peripheral cell for storafe in fat cells or metabolized by muscle.
CETP? where made? what does it do?
made in liver, transfers CE and TG b/t lipoproteins (direction determined by levels in donor and acceptor particles). But the major effect is to move CE from HDL to VLDL in exchange for TG. what happens if deficient? deficiency leads to high HDL CE, but not premature atherosclerosis
polygenic hyperXOLemia, cause, lipids, manifestations?
unknown genes, occurs in 5% of population, of which only a small % has FH, FDB, or secondary hyperXOLemia. Lipids LDL>220, type IIa or IIb. manifestations: atherosclerosis. how diagnose? differential diagnosis, so rule out others 1) If FH, 1/2 of 1st degree relatives have hyperXOLemia and xanthomas are frequent, 2)if FHCL, less than 10% of relatives have hyperXOLemia. 3)if VLDL is high, then it's FCHL
what is secondary hyperXOLemia? three dietary causes?
due to diet rich in XOL and saturated fats, which suppress hepatic LDL receptors. Also, hypercaloric diets stimulate VLDL production, and ethanol raises VLDL secretion (TG) and HDL. endocrine causes? DKA leads to excessive release of fatty acids, causing high TGs and VLDL synthesis. Type II DM causes high chylomicrons and VLDL due to decreased LPL activity. Also, insulin resistance stimulates hepatic VLDL synthesis, and down-regulates LD receptors. Hypothyroidism, Cushing syndrome (too much cortisol, or glucocorticoid treatment), and estrogen or oral contraceptive use has modest effecct, but exacerbate hyperTGemia.
LPL, located where?, how works?, req's what cofactor?,
on most tissues, especially adipose, muscle, cardium. gets secreted, attached to heparan sulfate on endothelium (is released by IV heparin (drug side effect)). cleaves FAs from TGs and p'lipids in chylomicrons and VLDL, which have on their surface ApoC-II (the req'd cofactor). What does a deficiency of LPL or ApoC-II cause? what happen during normal fasting? familial hyperchylomicronemia. During fasting, LPL activity in adipose decreases, but increases in muscle and heart
where's ApoA-I found?
HDL (stuctural). Where's ApoA-II found? HDL (unknown function)
what is the normal range for HDL?
should be 40 or above. HDL is inversely correlated with CHD. how does HDL levels change in women over time, and using HDL, what is a superior indicator of CHD risk? HDL decreases after menopause. LDL/HDL ratio is superior indicator than LDL or TC
evidence for LDL role in atherosclerosis?
high XOL in lesions, especially the foam cells and lipid pool; animals with lower XOL diets don't have atherosclerosis; epidemiological studies show correlation b/t XOL and atherosclerosis; migration studies of asians in U.S.; high LDL causes CHD in mice with LDL receptor deficiency; diet and drugs lower XOL, slows progression of atherosclerosis and CHD. what other lipoproteins are involved? high B-VLDL, TGs, and Apo-A II, but not chylomicrons, apoA-1 or LCAT. HDL reduces CHD.
what are borderline and high levels for TGs?
borderline 150-199, high 200-499. normal is below these, and very high is above these. how do CHD risk and TG levels correlate? High TGs go along with hypercholesterolemia most often, and so higher CHD, but independently, TGs don't cause atherogenenesis
cause, liporprotein changes, and manifestations of familial hyperXOLemia?
one of four disorders leading to hyperXOLemia. caused by mutated LDL receptor. results in high LDL and TC (type IIa hyperlipoproteinemia). chylomicrons aren't affected becuase even though they use LDL via ApoE, they have alternate receptors. HDL mildly reduced. manifestation is atherosclerosis and CHD in childhood, tendon xanthomas, esp achilles, hands, knees, and tuberous xanthomas, xanthelasma, corneal ring (arcus), and NB tendon xanthoma (only in FH and FDB. QUESTION... what are the population frequencies of FH and onset of CHD? homozygous 1:million, causes 6-10X increase in LDL, die in teens. hetero 1:500, causes 2-3 X increase in LDL, die in adulthood. TGs usually normal, HDL slightly reduced.
3 meanings of aretriosclerosis?
conventional (most prevalent, mainly from hypercholesterolemia, get plaques that may rupture); Restinosis injury (hardening secondary to stent placement, loss of elasticity, proliferation of smooth muscle cells, no XOL role); Graft atherosclerosis (after transplantation, chronic activation of T cells leads to atherosclerosis). Risk factors for conventional atherosclerosis? hypercholesterolemia, low HDL, HTN, smoking, DM, obesity, estrogen deficiency (menopause), family Hx of CHD, being male
what is an inherited hyperlipidemia of variable lipoprotein phenotype that is not stable over time?
familial combined hyperlipidemia (FCHL). (this causes combined hyperlipidemia along like dysbetalipoproteinemia) what are the characteristic changes in lipoproteins, and manifestations? incr. VLDL, and possibly LDL (and possibly LDL normal, but # particles increased (hyperapobeta-lipoproteinemia, incr apoB-100), low HDL. manifestations are high incidence of CHD, often with DM II, and syndrome X
stages of atherosclerosis?
1) adaptive intimal thickening by smooth muscle cells and proteoglycans at predilection sites 2) initial lesion (type I), microscopic accumulation of lipids in endothelium, macrophages recruited, take up oxidized LDL, turn into foam cells. 3) fatty streak (type II) raised lesions, mostly macrophage foam cells, intact endothelium, but surface expression different 4) intermediate lesion, pre-atheroma, translational (type III) more SMC in intima, and take up lipids, more extracellular conn tissue, fibrous cap forms, and apoptosis/necrosis of foam cells begins 5)atheroma, fibro-lipid plaque (type IV) eccentric lesion, thin fibrous cap, rich necrotic core, defects in endothelium, but no thrombi, permeable to macrophages 6) fibroatheroma (Type Va) thick fibrous cap, more collagen, (fibrous plaque, like type IV), capillary neovascularization in deep layers with infiltrating lipids, macrophages, t cells, immunoglobulin-rich 7) calcified plaque (type Vb) rich in extra- and intracellular Ca. 8) Fibrotic plaque (type Vc) mostly collagen, with little lipid, and 9) complicated plaque (type VI) same as V, but signs of hemmhorage (platelets, fibrin in lesion), fissure in cap, deep plaque erosion, ot thrombus. which lesions are "advanced lesions"? IV-VI
difference b/t men and women XOL, CHD, etc.?
men have higher TC until women, and women have less CHD until menopause. After menopause, TC and CHD increase markedly. Which is a better indicator of CHD, TC or LDL? LDL is a better indicator of CHD risk
besides upregulating stuff on arterial cells, what other effects does oxidation of LDL have on the cells?
many pathways are sensitive to oxidation, and regulate growth, differentiation, and death, so atherogenesis can result from stimulation of these pathways that leads to chronic inflammation, which goes along with impairment of NO dilation. what can be done to prevent this? low LDL, but also antioxidants (before lesions are formed)
where's ApoE found?
chylomicron remnants, VLDL, IDL, HDL (ligand for binding to LDL receptor LRP). where's Apo(a) found? Lp(a) (function unknown)
what are the causes, lipids, and manifestations of hyperchylomicronemia?
LPL or ApoC-II deficiency (freq 1:500), homozygotes only manifested, TG>1000, or even 10,000, high VLDL in elderly. fasting plasma stored in fridge is lactescent. since chylomicrons and VLDL also have XOL, TC is high too. signs/sxs are failure to thrive as infant, abdominal pain, pancreatitis, eruptive xanthomas, hepato- and splenomegaly. How does this affect CHD? no increase in CHD
formula to calculate LDL?
rationale is that VLDL is usually 1/5 of TGs, but if TG>400, it's not accurate. Levels also must be drawn on fasting, or else chylomicrons will be present
ApoE function?
recognized by LDL receptor (aka B/E receptor) for uptake of chylomicron remnants, VLDL, IDL, and HDL. what are the differences iin affinity of LDL receptor for ApoE, B, and variation in ApoE? receptor has much higher affinity for E than B. and hay three alleles for ApoE (E2, 3, 4), and therfore six phenotypes. E3 is by far the most common allele. E2 has low affinity (1% as much) if homozygous for E2, have dysbetalipoproteinemia. Interestingly, E4 homozygotes have higher risk of Alzheimer's
manifestations of atherosclerosis?
MI is often first sign. what are the various levels of onset of atherosclerosis in humans? starts in utero, depending on mother's diet. fatty streaks by age 10, aorta 30-50% covered by age 35. in cranial arteries, onset is much later and less extensive. Coronary arteries in myocardium free of lesions. branch points more common due to hemodynamics there.
what are lipoproteins?
complex particles that transport XOL and TGs through plasma. What are apolipoproteins? surface proteins on lipoproteins that help recognition and uptake of lipoprotein particles by cellular receptors or that convey enzymatic activity.
besides oxidation of LDL, what other factors promote lesion formation?
hemodynamic factors (changed gene expression by endothelium), physical damage, infectious agents (esp with TH1 response), chronic inflammation, HTN, DM, high reactive sugars. What immune responses are protective? TH1-> TH2 switch, antibodies to OxLDL (however responses to other antigens like heat shock proteins and chlamydiae make it worse).
besides diet and endocrine changes, what other things can lead to secondary hyperXOLemia?
liver disease (obstructive, cirrhosis, hepatoma, viral hepatitis), kidney disease (chronic uremia/dialysis, nephrotic syndrome), immune disease (systemic lupus erythematosus). What drugs can do this? thiazides, Bblockers, cyclosporin, tamoxifen, protease inhibitors
what is the exogenous pathway?
transport of lipids from intestine to peripheral tissues and liver. WHat is endogenous pathway? transport of lipids from liver to peripheral tissues
How does high LDL lead to foam cells?
it actually downregulates LDL receptors on macrophages, but LDL gets oxidized by proteoglycans in arterial wall, which oxidized LDL is then recognized by scavenger receptor A (SRA), CD36, and others. What effect does OxLDL have on arterial cells? upregulates adhesion molecules, cytokines, and growth factors by SMCs, macrophages, and endothelium.
biological roles of XOL?
modulates fluidity in cell membranes, helps form lipid rafts (along with sphingomyelin), precursor for hormones, corticoids, and bile acids, and it covalently modifies hedgehog to set up morphogen gradients.
three processes that regulate TC?
dietary intake, biliary excretion/elimination, de novo synthesis
XOL utilization, and elimination?
XOL cannot be broken down, but it is secreted by liver as VLDL, then half comes back as LDL. Steroid-producing tissues take up large amounts of XOL. reverse XOL transport important for homeostasis. How is XOL absorbed? solubilized by bile acids then absorbed. It is then either transported back into intestinal lumen, or esterified into chylomicrons (TG-rich). reverse transport back into intestine is important for XOL homeostasis, and to gaurd against plant sterols, and other things
ABC transporters?
ATP-binding cassette. They are either full or half transporters. ABCA1 is important for XOL efflux. ABCG5 and G8 are half transporters important for XOL homeostasis, and if mutated cause beta sitosterolemia (high plant sterols in the blood, aka pseudo FH). How are ABCs regulated? by LXR/RXR heterodimers. LXRs can be activated by oxysterols to inhibit XOL absorption
major source of endogenous XOL?
is LDL, taken up into cells by LDL receptors upregulated when XOL is low. The opposite happens when XOL is high. What other change occurs to limit XOL when it's high in cells? upregulate XOL export via ABC transporters, which pass on XOL to ApoA-I, which is located primarily on HDL. LCAT also assists.
how do macrophages differ in their regulation of XOL?
they take up toxic levels of LDL via scavenger receptors (SR-A), which are not down-regulated by high XOL. This built-in protection shows that down-regulation of XOL synthesis and LDL receptors isn't enough to control XOL levels. What is the significance of ABCA1 in macrophages? it helps efflux XOL to extracellular acceptors, and if mutated (tangier's disease), macrophages build up huge levels of XOL (yellow tonsils, xanthomas). HDL is also low in tangier's, which shows that ABCA1 is important to help load XOL onto HDL. Reverse transport is enhanced by ApoE on macrophages (great ligand for LDL receptor)
what is ACAT? what does it do?
esterifies XOL so it can be stored in a non-toxic form in lipid droplets
these help maintain intracellular XOL homeostasis. SRE is sterol regulatory element, and the BP is the binding protein. XOL inhibits SREBP, which binds to promotors for FPP synthase (to make farnesyl pyrophosphate), squalene synthase, and HMG CoA synthase and reductase (as well as LDL receptor). How are these a neg feedback system? HMG CoA synthase and reductase, as well as geranyl-to-farnesyl pyrophosphate, and squalene, are all steps in XOL synthesis.
physical nature and location of SREBPs?
synthesized as inactive, integral membrane proteins in the ER, with both the N and C termini in the cytoplasm. How do they exert their effects? when XOL is low, a second ER protein, SCAP (SREBP cleavage-activating protein) comes into contact with SREBP, and directs it to the golgi where it's acted upon by Site1 protease (cleaves the linker), followed by cleavage of the n-terminus by a second protease, freeing the HLH-zip domain to enter the nucleus, bind the DNA, and promote transcription
what does Insig do?
In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage activating protein) and Insig-1. When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the Golgi apparatus
how are LXR/RXR nuclear receptors involved in XOL homeostasis?
ligands of either LXR or RXR can activate the heterodimers to promote the transcription of Cyp7A (for bile acid synthesis), SREBP, ABC sterol transporters (in both intestines and macrophages). what are ligands for LXR and RXR? LXR includes the oxysterols 22OH XOL and 25OH XOL (which accululate when intracellular XOL is high). RXR ligand is 9-cis retinoic acid