Final & Midterm 1 Flashcards
mTOR
activated by leucine and growth factors (insulin), inhibited by AMPK, phosphorylates 4E-BP and S6K –> promotes protein synthesis
eIF2
When GTP bound, eIF2 mediates the formation of 43S pre initiation complex, if eIF2 is phosphorylated it will be trapped in inactive/GDP bound form - eIF2 acts as “brakes” to stop protein translation if anything goes wrong
“brakes” of protein translation
eIF2
PERK
phosphorylates eIF2 during ER stress
GCN2
phosphorylates eIF2 during nutrient limitation
eIF4F
complex that binds to cap of mRNA and drives protein translation, acts as “gas pedal”, part of the complex (eIF4E) can bind to 4E-BP which rate limits
4E-BP
protein that binds part of eIF4F complex to prevent protein synthesis, is phosphorylated/deactivated by mTOR
Rheb
small GTPase that activates mTORC1, is stimulated by nutrients
TSC1/C2
inhibits Rheb so inhibits mTORC1, TSC1/C2 is inhibited by insulin
LCAT
enzyme that converts free cholesterol into cholesteryl ester, which is then sequestered into the core of a lipoprotein particle
“gas pedal” of protein translation
eIF4F complex
PKR
phosphorylates eIF2 and stops protein synthesis, kinase secreted by cancer/tumors
Akt
phosphorylates TSC2 which inactivates the complex
AMPK
activated by rising AMP and falling ATP, activation of AMPK activates TSC1/2, switches on catabolic pathways and switches off anabolic pathways (such as inhibition of ACC leading to decrease malonyl-CoA levels and increased mitochondrial beta oxidation)
Berberine and EGCG
compounds that activate AMPK
Autophagy
process that targets cellular components for lysosomal degradation in response to cellular damage and starvation
Sirtuins
NAD+-dependent protein deacetylases that mediate many of the effects of caloric restriction, they can act as nutrient sensors
Activation of sirtuins
positive impacts on metabolism including enhanced fatty acid oxidation and gluconeogenesis (liver), increased mitochondrial activity and insulin sensitivity (muscle), and improved glucose-induced insulin release (pancreas)
Components of circadian clock
CLOCK/Bmal1 drive the expression of circadian genes and the repressors Cry and Per. Cry/Per bind and inhibit CLOCK/Bmal1.
functions of circadian clock
The clock is reset through ubiquitination and proteosomal degradation of the repressor complex. Circadian rhythms establish cyclical acetylation of chromatin with CLOCK
acting as acetylase and Sirt1 as deacetylase (Sirt1 represses circadian gene expression)
nuclear receptors affecting circadian rhythm?
nutrient sensing by nuclear hormone receptors: PPAR α can activate the expression of BMAL and both PPARϒ or -α can bind to the REV-ERB promoter
Hepcidin
prevents uptake of iron by degrading ferroportin, trapping iron in the intestine
Anemia of chronic disease
Pro-inflammatory cytokine (IL-6) causes large secretion of hepcidin which leads to reduced circulating iron levels (defense against microorganisms need for iron)
Hereditary iron overload disease
Mutations in HFE, TfR2 or hepcidin can lead to iron overload
Ferritin
a shell like protein that can store up to 4500 Fe atoms, can store and release iron in a controlled fashion and act as iron storage buffer
HFE
transferrin bound iron with a protein called HFE (High Fe) interacts with TfR2 which leads to secretion of hepcidin (peptide hormone).
transferrin
circulating Fe3+ is bound to transferrin and delivered to tissues
IRE
Iron response elements (IREs) - hairpin structure in non coding regions (untranslated region or UTR) of mRNAs for proteins like TfR and ferritin… binding of IRPs to ferritin 5’ inhibits translation, binding of IRPs to TfR 3’ stabilizes the mRNA and promotes translation
Results of low iron
Active IRPs, ferritin is down regulated (don’t need storage) and TfR is upregulated (cells have more receptors to take in iron)
SREBP
sterol regulatory element-binding proteins - Transcription factor that regulates expression of genes involved in cholesterol and lipid synthesis
how does CR activate sirtuins?
CR may activate sirtuins by changing the redox balance between NADH and NAD+. Alternatively, CR may decrease nicotinamide (a product and inhibitor of
SIRT1 catalytic activity)
Activators of SIRT1
resveratrol, cause partial protection from effects of high fat diet
Scap
S-cleavage activating protein binds to SREBP, has sterol-sensing domain
In sterol-depleted cells:
Scap/SREBP complex starts to bind to Sec24 - component of CopII protein coat. Proteases (only in Golgi) S1P and S2P cleave SREBP in 2 places, freeing the active transcription factor (nuclear form). The cleaved SREBP can form dimers and go to nucleus to target lipid metabolism genes
High cholesterol conditions:
Cholesterol binds to Scap’s sterol-sensing domain which causes a conformational change → prevents interaction with CopII protein. ER retention of Scap/SREBP is enhanced by binding to the ER protein Insig (Insig is a SREBP target gene - SREBP induces the expression of its own negative regulator)
Convergent feedback inhibition
Newly supplied cholesterol and newly synthesized Insig blocks SREBP from going to nucleus
Insig
protein that keeps SREBP in the ER during high cholesterol, during low cholesterol Insig is ubiquitinated and degraded
HMG CoA reductase
first enzyme in cholesterol production pathway, transcription is stimulated by SREBP, enzyme is bound to ER membrane and rapidly degraded in presence of lanosterol, inhibited by AMPK
Obesogens
Foreign chemical compounds that disrupt normal development and balance of lipid metabolism, obesogens that target the PPARγ/RXR complex mimic the metabolic ligands and activate the receptor leading to upregulation of lipid accumulation which explains their obesogenic effects.
Similarities/differences between HMG CoA reductase and SREBP
Both bind to Insig, but SREBP is retained in ER and HMG CoA reductase is degraded
Effects of obesogens
- Endocrine disruptions-sex steroids
- Hormone dysregulation-cortisol, adiponectin, and leptin
- Adipogenic gene upregulation- adipocyte growth
- Epigenetic Effects
Adiponectin
Activates glucose transport/inhibits gluconeogenesis via AMPK, activates fatty acid oxidation and decreases inflammation through PPARα pathway, enhances insulin sensitivity through phosphorylation of insulin receptor and IRS-1.
So adiponectin is a good thing, and decreasing this hormone can lead to obesity.
Lipoproteins
Lipoproteins are macromolecules consisting of an outer soluble lipid-protein shell enclosing a droplet of insoluble lipids
Chylomicrons
transport fat from the intestines into the bloodstream
ApoC-II
ApoC-II activates lipoprotein lipase which catalyzes hydrolysis of TG
ApoB48/remnant receptor
takes leftovers/chylomicron remnants back into the liver
Lipoprotein lipase
catalyzes the hydrolysis of TG
Familial chylomicronemia syndrome
extremely elevated levels of TG in the blood, can occur due to lipoprotein lipase deficiency or ApoC-II deficiency
Mendelian randomization
can be used to predict clinical effects of therapeutic intervention on disease biomarkers
Familial hypercholesterolemia
caused by defects in LDL receptor
Nampt
activated by caloric restriction, which decreases nicotinamide levels and increases Sirt1 activity
CPT1
helps with fatty acid oxidation
ApoA1
component of HDL, activates LCAT
ABCA1
transports cholesterol out of cells
SR-B1
transport cholesterol out of cells?
ApoB100
synthesis of VLDL, in liver
ApoB48
synthesis of chylomicrons, in small intestine
IDL
VLDL remnant
ApoE
picked up in circulation, ligand for ApoE receptor
ApoA-5
promotes VLDL breakdown
ApoCIII
impairs VLDL clearance (inhibits LPL)
Hepatic lipase
converts IDL to LDL
PCSK9
A protein secreted by the liver that targets LDL receptors to lysosomes for degradation
