Nutrition part 2 Flashcards
BMI (body mass index)
scale used to measure/quantify “adiposity” (just an estimate, bc not specific to body fat in calculation)
* weight lifters can have falsely high BMI, *doesn’t apply to children – use separate chart (age and sex adjusted)
BMI= mass (kg)/(height (m)^2)
VLDL
Produced in liver,
Carries triglycerides and cholesterol to extra-hepatic tissues.
ApoB-100…+ApoC II and ApoE
Cholesterol biosynthesis
Energetically demanding,
Get Cs from acetyl CoA
Uses 6 ATP and I NADH, also: HMG-CoA Reductase,
* dolichol, heme A, and ubiquinone
Rate limiting step of cholesterol synthesis
HMG-CoA Reductase, in ER Limited by: - gene transcription - protein turnover - post translational modification Feedback regulation: cholesterol
HMG-CoA Reductase regulators
inhibition: AMP-activated protein kinase (+AMP, + sterols)
Activation: phosphatase (+insulin)
Sterol regulatory binding protein (SRBP)
Transcription factor in ER…
When low cholesterol: moves to Golgi, gets cleaved by proteases, goes to nucleus and stimulates expression of HMG-CoA reductase gene
Statins
Medication type used to lower cholesterol,
= competitive inhibitor of HMG CoA Reductase
(AND promotes SREBP via cholesterol feedback loop –> increase LDL receptors and cholesterol uptake by cells)
ie: Lipitor, zocor, lovastatin
Lipoprotein
Soluble, specialized lipid transport molec.
= amphipathic alpha helix (proteins to outside, lipids to middle)
Structural components: apolipoproteins (“baggage tags”)
- ApoA, ApoB, ApoC, etc
4 types of cholesterol (sizes)
VLDL- very low density 0.95-1.006. Trig.
IDL - intermediate density 1.006-1.019.
LDL - intermediate density 1.019-1.062. Cholesterol esters and cholesterol
HDL - high density 1.062-1.210. Cholesterol ester and cholesterol.
*each with own apolipoprotein
Chylomicron
Smallest lipoprotein, Produced in intestinal enterocytes, Carries triglycerides and cholesterol (from small intestine to organs) ApoB-48 ... + ApoC II and ApoE
LDL
Made from VLDL when lose triglyceride.
Main carrier of cholesterol and cholesterol esters to peripheral tissues or liver for excretion.
HDL
Produced in liver and intestine.
* for reverse cholesterol transport!
(Exchanges apolipoproteins and lipids between particles)
Uses ApoA I, ApoC II, and ApoE
Lipoprotein lipase regulation
activated by ApoC-II
(*ApoC-II repressed in fat during fasting but NOT in m)
Also: gene expression… + insulin, feeding; - fasting
(LPL= enzyme to convert cholesterol from VLDL to fatty acid and monoacylglycerol)
Reverse cholesterol transport
By HDL,
Transport of cholesterol back to liver to be excreted
*exchanges from tissue to LDL (transporter) via cholesterol ester transfer protein (CETP)
ATP-binding cassette protein
Required by HDL to get cholesterol from tissue,
(So can send back to liver)
Powered by ATP hydrolysis,
Transports cholesterol from inner leaflet of plasma membrane to outer leaflet
LCAT (lecitin:cholesterol acetyl transferase)
Enzyme on HDL that converts cholesterol from tissue (from ABC protein),
Converts to cholesterol ester
Foam cell
A macrophage engorged with lipids.
First gross indicator of atherosclerosis
Nitrogen balance
Nitrogen taken in should equal nitrogen lost
In: digestion and AA absorption
out: excreted in urine (urea and ammonia) and and lost in skin and feces
*to maintain free AA pool
Types of Nitrogen IMbalance
Positive - childhood growth, lactation, injury recovery
Negative = (1 or more AAs missing from pool; cannot replace normal protein loss) – traumatic injury, cancer, malnutrition
* Cachexia: - N bal.–> muscle loss, fatigue, etc.
— NOt fixable by diet (from cancer, AIDs, trauma, etc)
Kwashiorkor
Severe protein insufficiency,
w/ moderate energy intake
–>edema,
Permament growth stunting, mental disability
Marasmus
Severe protein AND energy insufficiency,
Little muscle mass, little/no fat, poor strength
Permanent growth stunting, mental disability
Transport of nitrogen through body
In form of AAs (esp. Ala, glut)
Bc ammonia and urea = toxic
– conversion to ala/glut by transaminases (swap amino grps)
(Works for all AAs except lysine and threonine)
* Vit B6 = cofactor
Glutamine synthetase
Makes glutamine from NH4+ and glutamate, uses ATP
In peripheral tissue and muscles
(Reverse once in liver = glutamate dehydrogenase)
Glutaminase
Converts glutamine to glutamate and ammonia
in liver, kidney
(= reverse of glutaminase rxn, used to convert glut from transport back to useful molecs – esp. glutamate)
N-acetylglutamate
Allosteric regulator (Activator!) of carbamoyl phosphate synthetase, When glutamate and acetyl CoA are high
*argenine activates N-acetylglutamate synthesis
PRPP
5-phosphoribosyl-1-pyrophosphate,
Activated ribose sugar ring for nucleotide synthesis (de novo or salvage)
ribose-5-phosphate –(PRPP synthetase)–> PRPP
rib-5-PO3 = from pentose phosphate pathway
Purine biosynthesis
Built directly onto PRPP backbone;
Requires 3 AAs, CO2, and 10-formyl THF (donates 2 Cs).
uses 6 ATP to drive
PRPP –> IMP –> AMP or GMP (—> ATP/GTP)
- feedback reg. to IMP and + cross-reg. to AMP/GMP
Regulation of purine biosynthesis
Complex,
positive and negative allosteric feedback regulation.
Mostly negative feedback at IMP (before branch),
Positive Counter-regulation btwn 2 branches maintains balance btwn ATP and GTP branches.
Pyrimidine biosynthesis
First assemble base, then attach to PRPP.
UMP is 1st product,
Carbamoyl phosphate synthetase II
Enzyme in cytoplasm,
Makes carbamoyl phosphate
(For combination with Aspartate to make Pyrimidine ring)
blood-brain barrier
keeps toxins out and allows selective transport, w/ P450 drug metabolizing system (–> enzymatic barrier).
*restrict AA passage
Special transporters:
- low Km glucose transporter
- essential Fatty acid transporters (NO non-essential FA uptake)
- ketone body transporters
energy to brain from…
glycolysis, TCA, and oxidative phosphorylation
–> take in as glucose
Starvation: ketone bodies (*no energy storage IN brain)
also: need sphingolipids for myelin.
essential fatty acids
omega 3s and 6s
can’t boisynthesize these bonds
how P450s detoxify
make soluble by adding hydoxyl and/or ketone groups
if make polar => soluble, so can excrete by body
sphingolipid
amphipathic lipid molec,
made on serine backbone,
built onto ceramide.
* important in brain as myelin component!
AAs in brain
used as NTs or to make NTs,
so restricted passage across Blood-brain barrier
(so don’t interfere w/ signaling)
*aminotransferases - enzymes to convert btwn AAs (make into NTs)
alternate name for aminotransferase
transaminase
enzyme, converts btwn 1 AA and another
* for nitrogen transport*
ATP yield from substrate-level phosphorylation
2 ATP
makes 4, uses 2
RBC (aka erythrocyte) metabolism
Glycolysis and substrate-level phosphorylation ONLY
(bc no mitochondria)
* use lactate dehydrogenase to regenerate NAD+
* pentose phosphate pathway: use some glucose to make NADPH
- recycle lactate to liver for gluconeogenesis (Cori cycle)
ALSO: side rxn makes 2,3-BPG (lower O2 affinity)
2,3-BPG (Biphosphoglycerate) in RBCs
negative allosteric regulator (lowers hemoglobin affinity for O2)
- made in side rxn of glycolysis
pentose phosphate pathway in RBCs
uses glucose (small percent of total) to make NADPH
- need NADPH for glutathione recycling
- –> protection against ROS, etc.
Glutathione
compound used to protect against damage from ROS.
ie: in RBCs
* to recycle: need glutathione reductase and NADPH
- –> deficiency => acute hemolytic anemia
iron deficient anemia
from low concentration of hemoglobin in RBCs (–> smaller)
– need more Fe (from diet)
megaloblastic anemia
RBCs = immature.
from folate or Vit B12 deficiency
(needed for dNTP synthesis)
acute hemolytic anemia
deficiency in glucose-6-phosphate dehydrogenase
–> low NADPH
(so problem in pentose phosphate pathway to make glutathione)
hemochromatosis
genetic mutation in ferroportin
(transfers Fe from intestinal enterocyte to blood stream)
- most common genetic disease in human population
enzyme that makes dTMP from dUMP
Thymidilate synthase
heart metabolism
energy sources:
- Fatty acids (even in fasting!) –> beta oxidation
also: glucose, lactate, ketone bodies (glycolysis, TCA, Ox. Phos.)
- get FAs from chylomicrons or VLDLs via lipoprotein lipase
heart metabolism under stress
has special PFKFB (“bifunctional enzyme”) isozyme stimulated by epinephrine,
inhibits biphosphatase activity
–> increase preference for fructose-2,6-biphosphate
(promote glycolysis)
skeletal muscle metabolism (general)
1 fuel: glucose (from glycogen and FAs)
~major storage site for glycogen (breakdown = glycolysis)
prolonged exercise: Beta Oxidation
starvation: FAs and ketone bodies as fuel.
–> mm. tissue degraded for AAs (for gluconeogenesis)
Anaerobic Exercise
fuel sources:
- glucose from ANaerobic glycolysis (substrate-level phosphorylation, from glycogen stores)
- recycle lactate to liver for gluconeogenesis (Cori cycle)
- phosphocreatine (from stores, SHORT burst energy)
creatine biosynthesis
3 steps – stored in mm. as SHORT energy burst source
- kidney
- liver – methylated by SAM (S-adenosyl homocysteine)
* need Vit B12 as methyl donor to SAM* - target tissue (brain, heart, skeletal mm.)
Early aerobic exercise (metabolic process in skeletal muscle)
– adequate glycogen stores–
breakdown glycogen into glucose to use in TCA/ox. phos.
- -> TCA generates acetyl CoA –> Citrate
1. citrate leaves mitochondria
2. binds to acetylCoA Carboxylase (“ACC-2”)
3. synthesize Malonyl CoA
4. negative allosteric regulation of FA Oxidation
Malonyl CoA
allosteric effector, limits/slows Fatty Acid oxidation.
– made in skeletal muscle by ACC-2 (acetylCoA Carboxylase),
during Aerobic exercise
(when glucose levels from stored glycogen = adequate)
Late Aerobic exercise (metabolic process in skeletal muscle)
– glycogen stores in m. = depleted–
- AMP levels rise
- activate AMP-activated Protein Kinase
- a) inhibit ACC-2; b) activate MCoADC
- lower conc. Malonyl CoA
- increase Beta Oxidation (by stopping inhibition)
Exocrine Pancreas
secretes hydrolases for food digestion
– released in form of zymogens (proenzymes),
then cleaved into active form in duodenum.
endocrine pancreas
secretes hormones for energy regulation/glucose homeostasis
- Beta cells: insulin
- alpha cells: glucagon
small intestine
2 jobs:
- produce digestive enzymes (from mucosal cells)
- absorb nutrients
- most via Na+ co-transporters
- fats into cholemicrons
effect of insulin on white adipose tissue
2 effects:
1. promote glucose uptake
(promote translocation of GLUT4 to membrane)
2. increase lipid uptake
(increase expression of Lipoprotein Lipase (“LPL”))
adipokines
hormones that control energy homeostasis,
released by adipose tissue (endocrine function).
ie: Leptin
Liver - uses in metabolic processes
- maintain glucose homeostasis (esp. via glycogenolysis and gluconeogenesis)
- Ketone Body formation
- Urea formation, detox (via P450 enzymes)
- control cholesterol levels (excretion, make VLDLs)
metabolism in liver
glucose uptake proportional to serum glucose levels (GLUT2 => high Km)
glucose –> glucose-6-phosphate
fed state: TO glycogen stores, glycolysis, or pentose phosphate pathway
starvation: …
Mc3r vs. Mc4r
melanocortin receptors on neurons of hypothalamus,
receive satiety signals (MSH from POMC neuron).
(energy homeostasis)
Mc3r: increase energy expenditure AND reduce feeding
Mc4r: only reduce feeding
POMC neuron
neuron in arcuate nucleus, receives SATIETY signals from body.
releases MSH to Mc3r/Mc4r – + to hypothalamus (decrease feeding), - to AGRP/NPY neuron.
+ stimulation: insulin and leptin
AGRP/NPY neuron
neuron in arcuate nucleus, receives HUNGER signals from body.
Sends NPY and AGRP to neuron receptors in hypothalamus to increase feeding, inhibits POMC and Mc4r receptor(s).
+ stimulation: Ghrelin
- inhibition: PYY, CCK, GLP-1; insulin and leptin
Ghrelin
HUNGER signal molec made in stomach, sent to hypothalamus to INCREASE feeding. (the ONLY hunger stimulator)
+ to AGRP/NPY neuron
* levels increase w/ weight loss (hard to lose), BUT deacrease and stay low w/ gastric bypass
PYY
satiety signal molec, *released in proportion to lipid intake
made in GI tract,
to hypothalamus to INhibit AGRP/NPY neuron(s)
* inhibit Hunger signal, –> indirectly increase satiety signal
CCK (cholecystokinin)
satiety signal molec,
made in GI tract,
to hypothalamus to INhibit AGRP/NPY neurons
AND to pylorus –> close sphincter, so stomach fills up
*Inhibit Hunger signal, –> indirectly increase satiety signal
GLP-1
satiety signal molec,
made in GI tract, sent to hypothalamus;
INhibits AGRP/NPY neurons
(inhibit hunger signal) –> indirectly increase satiety signal
AND: suppress glucagon secretion, delay gastric emptying
Insulin
energy homeostasis regulating molec,
made in pancreas (beta cells), sent to many parts of body, including hypothalamus.
+ POMC neuron –> increase satiety
- AGRP/NPY neuron –> block hunger signal
Leptin
satiety signalling molec made in adipose tissue (“adipokine”),
sent to hypothalamus as satiety signal.
+ POMC neurons –> increase satiety
- AGRP/NPY neurons –> decrease hunger signal
MSH (melanocyte stimulating hormone)
* f(x) in hypothalamus
(among other f(x)s…) for energy homeostasis:
works as ~neurotransmitter for POMC/CART neurons
binds to Mc3r and Mc4r receptors on hypothal. neurons.
* carries SATIETY signal
adiposity signals
"long-term" signals, respond to levels of adipose store size *leptin *insulin -- slower pathway
short term appetite signals
Released by GI tract to regulate meal size,
*CCK, PYY, GLP-1 (satiety)
*Ghrelin (hunger)
work over course of minutes - hours
leptin problems in overweight individuals
- losing weight: when adipose levels decrease, leptin decreases.
fewer satiety signals –> increased appetite (bio reason: HARD to lose weight) - in obese: high fat so high leptin levels, BUT –> leptin resistant!
(lose some satiety signaling!)
obesity genes
- Ob (“obese”) –> leptin. CAN use leptin replacement therapy on humans to fix problem.
- db (“diabetes”) –> leptin receptor. insulin and leptin resistant. Rare in humans.
- POMC/Mc4r mut. –> (AD) unique early-onset obese shape, red hair, adrenal insuff.
- Downstream muts: to hypothalamus for regulation (SIM1, BDNF, TRKB), rare.
Problems treating obesity w/ addl leptin
more leptin should increase satiety signals.
BUT leptin levels already high in obese!
– leptin resistant, so no change w/ leptin therapy!
(in general population, some specicial genetic cases DO benefit)
Complex trait
affected by multiple genetic factors, (no 1 = decisive).
often includes genetic and environmental factors;
prevalence = bell curve, often threshold –> affected.
ie: common obesity
NOT mendelian inheritance
Genome wide association studies (GWAS)
- find SNPs in genomes of many individuals
- compare SNP presence in groups of population with phenotypes
- -> are there SNPs common across obese ppl in a population? - calculate relative risk based on variants for unaffected vs. affected groups
genes associated w/ obesity from GWAS
(only modest connection)
- INIG2
- FTO –> leptin expression and localization of leptin receptor in hypothalamus (cilia)
syndromes w/ obesity
- Prader-wili: excess ghrelin –> insatiable hunger
- Bardet-Biedl: (ciliopathy) AR, multi-gene. Polydactyly, decreased leptin receptors –> poor leptin response
- 16p11.2 deletion (autism) –> high rate obesity, mech unknown.
* FTO gene intact! (not deleted)
types of gastric bypass surgery
- roux-en-Y (most successful) - bypass stomach completely (sm. intestine instead)
- adjustable gastric banding - restrict size of stomach opening
- gastric sleeve - reduce size of whole stomach (remove large portion)
Insig Complex
binds cholesterol,
then associates with membrane bound portion of HMG-CoA reductase
–> degrades the protein!
(- regulator of HMG-CoA Red.) –> inhibits cholesterol biosynth.
“free” fatty acids
bound to albumin or other serum proteins when travel in blood from adipose tissue to liver,
“free” bc not esterified
Greatest risk determinant for atherosclerosis
Low HDL!
High LDL is also bad, but not as strong in changing risk
Process and players for cholesterol reverse transport
- ABC-A1: move cholesterol from inside to outside of cell membrane
- HDL accepts cholesterol
- LCAT converts to chol. ester
- HDL passes chol. ester to LDL via CETP (swap w/ trigl.)
(LDL carries to liver from tissue)
Cholesterol
Nonpolar lipid molec, mostly in plasma membrane, ER or inner mitochondrial membrane.
*excess –> atherosclerosis
Cholesterol ester
A cholesterol molec esterified with a fatty acid,
– By ACAT enzyme
ALT (alanine aminotransferase)
Enzyme to convert glutamate to alanine,
Uses pyruvate, Vit B6
*reversible in liver, to break back into glutamate and pyruvate,
(Used for N and energy purposes)
Glutamate dehydrogenase
Mostly used to convert glutamate to alpha ketoglutarate in liver, using NAD+ or NADP+.
But: can also use for reverse to harvest nitrogen from liver:
alpha-ketoglutarate –> glutamate (synthetic rxn)
Urea cycle
Combines arginase, bicarbonate and NH3 to make urea.
(For excretion of Ns), driven by ATP
Carbamoyl phosphate synthetase = rate limiting step, ornithine to citrulline.
CPS = allosterically regulated.
(Next: citrulline -> arginosuccinate -> arginine -> urea, ornithine)
Regulation of carbamoyl phosphate synthetase I (and urea cycle)
N-acetylglutamate (NAG): + allosteric regulator of CPS
- **needed for CPS to work!
- arginine = + allo. reg. of NAG
- all urea synth. enzymes = induced (+) by prolonged fasting OR excess intake
Purpose of urea cycle
- Excrete excess nitrogen (in form of urea)
2. Generate arginine (!)
Common features of urea cycle disorders (“UCDs”)
Mostly Aut. Rcessive; = Accumulation of NH3, affects CNS
Symptoms: Agitation, hyperventilation, coma, death.
Treatment: protein restriction, N scavengers, Na phenylbutyrate,
— sometimes supplement arginine (for homeostasis)
** OTC def. = most common*
Mitochondrial urea cycle deficiencies
NAGs/CPS-1/OTC (all): decreased citrulline and arginine
NAGs/CPS-1: No orotic aciduria
OTC: marked orotic aciduria
OTC transports ornithine across membrane into cytosol
Cytosolic urea cycle deficiencies
AS (“cittrullinemia”): highly elevated citrulline
AL: high arginosuccinic acid (“ASA”), mod. elevated citrulline, less orotic acid
Arginase: very high serum arginine
**AL and arginase def. = less toxic
Screening for UCDs in newborns
CAN detect for AS, AL, arginase, and HHH deficiencies
CanNOT detect for NAGs, CPS-1, or OTC deficiencies
To test: try RBCs, fibroblasts enzymes, or gene testing
Phospholipid structure
amphipathic molec, (like triglyceride);
Glycerol backbone with 2 fatty acid tails (hydrophobic) and one “head group” (hydrophilic).
precursor: phosphatidate (same as trigl.), *use CTP in biosynth.
phospholipid function
= main structural unit of membranes;
ex:
- phosphatidylserine = apoptosis signal in plasma membrane
- phosphatidylcholine = in lund surfactant,
* mut–> respiratory distress syndrome
phosphatidylserine
a phospholipid molec,
used in plasma membrane as apoptosis signal.
normal: on inner leaflet of membrane
pre-apoptosis: moved to outer leaflet of membrane
(now accessible for binding)
sphingolipids structure
lipid molec made on sphingosine “backbone,”
1 fatty acid tail and 1 “head group” (= carbohydrate in glycolipids);
precursor: ceramide
degradation: in lysosomes, freq. mutation
(ie: Tay Sachs, get neuro accumulation of lipids)
Sphingolipids function/use
a lipid membrane component,
- common in lipid rafts – for intercellular signaling;
- sphingomyelin = common nerve covering
- determines blood type (A, B, AB, O)
Blood types mechanism
4 types (A, B, AB, O)
A: GalNAc transferase adds A substance
B: Gal transferase adds B substance
AB: has Gal AND GalNAc, which add A and B substance
O: has neither transferase (no substance added)
lysosomal storage defects
mutations in pathway to degrade sphingolipids in lysosomes,
causes dangerous accumulation of intermediates (esp. in brain).
–> get disease
(ie: Tay Sachs)
eicosanoids
lipid signaling molecs, regulate cell f(x) and modulate inflammatory response; immediately released (not stored), act locally. 2 types: prostaglandins, leukotrienes *biosynth. precursor = arachidonic acid OR others
prostaglandin synthesis (eicosanoid)
precursor: arachidonic acid (or other) enzyme
1. phospholipase A: converts to 5C ring.
- – most regulated step in eicosanoid OR lipid synthesis
2. cyclooxygenase: uses COX1 or COX2
3. PGG2: metabolized into amny diff. 2nd messengers
methionine synthase
enzyme to convert homocysteine to methionine
(met. = methyl donor for many rxns)
** needs cobalamin as cofactor!
SAM (s-adenosyl methionine)
activated form of methionine (ready to donate methyl).
methionine + adenosine –> SAM …
–>SAM - CH3, - adenosine => back to homocysteine.
Ex. uses of SAM:
donate CH3 to make epinephrine, melatonin, creatine…
3 phases of cobalamin (vit B12) absorption
- Gastric Phase: release B12 from protein
- Luminal Phase: IF secreted, binds B12
- Mucosal Phase: IF-B12 complex binds to receptor,
- -> transport B12 across membrane to capillary bed
* bound by transcobalamin in blood
Intrinsic Factor (“IF”)
a glycoprotein esp. resistant to proteases,
secreted from parietal cells in stomach.
* binds to B12 to protect and transport to capillaries
(IF-B12 complex binds to receptor in ileum)
excretion of cobalamin
(vit B12)
excreted via bile,
but much = re-absorbed
–> stored in body for months or years!
pernicious anemia
–> vit B12 deficiency,
when parietal cells do NOT secrete IF, so B12 not transported to capillaries.
* affliction increases w/ age (bc lose parietal cells)
Folate
nutrient,
bio. precursor to THF (“tetrahydrofolate”).
* folate –(dihydrofolate reductase, NADPH)–> THF*
(THF = methyl donor, ie: for cobalamin –> methionine)
THF (tetrahydrofolate)
bio molec made from folate, = 1 C carrier (for metabolism).
used as methyl donor for vit B12 –> methionine, and glycine biosynth.
* helps make dTTP for DNA synthesis too!
(folate –(dihydrofolate reductase, NADPH)–> THF)
dihydrofolate reductase
enzyme to convert folate to THF.
* uses NADPH
(THF = methyl carrier/donor for many body rxns)
consequences of folate deficiency
Folate specifically:
1. increased risk for neural tube defects
Shared btwn Folate and Vit B12 deficiencies:
2. increase risk for heart disease
3. megaloblastic anemia (enlarged WBCs and RBCs)
symptoms of B12 deficiency
- megaloblastic anemia (enlarged WBCs and RBCs)
- Neural deficits (memory loss, slowness, numbness/tingling) - from nerve demyelination
* hard to distinguish from old age!
* ** pernicious anemia = 1 cause of vit B12 deficiency
Anapleurosis
the process of replenishing carbons to TCA cycle
particularly in brain, bc some alpha-ketoglutarate goes to make glutamine – NT
