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BIOC 311 > Hormonal Regulation > Flashcards

Hormonal Regulation Flashcards

1
Q

What different factors are considered in transcriptional control ?

A
  1. Events UPSTREAM of transcriptional activity which define the signals involved and their activation
    - Ex of signal: Insulin, Glucagon, Glucocorticoids, Nutrients
    - Ex of Activation/route: signalling pathways, protein cleavage, direct activation
  2. The molecular MECHANISM by which transcription factors regulate gene expression
    - Ex: Recruitment of coregulators, corporation with other TF, etc.)
  3. Events DOWNSTREAM of transcription, which depend on the genes being targeted and which further signals are generated
    - Ex: expression of metabolic enzymes or a cascade of regulators
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2
Q

What is CREB?
What are its family members?
How are they Activated?
What pathway do they regulate

A

CREB = cAMP Response Element Binding

Family members → CREM, ATFI
- Leucine Zipper Transcriptional factors
- Activated by PTM via phosphorylation
- Glucagon → increase cAMP levels → activates PKA → phosphorylation of CREB
- They are considered as “first responders” in activation of gluconeogenesis

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3
Q

What is SREBP-1c?
How are they Activated?
What pathway do they regulate

A

SREBP-1c = Sterol Response Element Binding Protein
- bHLH-Leucine Zipper Transcription Factor
- Targets genes involved in lipid metabolism
- Activated by PROTEOLYTIC CLEAVAGE → stimulated by sterols and unsatruated FAs (allosteric control for both)

  1. Signal (inside) → Sterols keep SCAP-SREBP in the ER bound to Insig
  2. Activation → In the Golgi, S1P cleaves SREBP
  3. Transcription → S2P cleaves bHLH → goes to the nucleus → Lipogenesis
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4
Q

What mechanisms are involved in short-term regulation or metabolic pathways?

A

Short-term = seconds-minutes
- Allosteric control
- Post-translational modifications (ex: Phosphorylation)

In response to chanes in the levels of metabolites or hormonal signals
Ex: Glycogen phosphorylase is sensitive to intracellular levels of AMP and phosphorylation in response to glucagon
*Acts in coordination with logn-term regulation

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5
Q

What mechanisms are involved in long-term regulation of metabolic pathways?

A

Long-term = hours-days-seasons-years → fasting/feeding, exercise, circadian clock, development (zygote → old age)

  • Transcriptional regulation or metabolic genes → involves changes in activity of metabolic transcription factors
  • Requires the signal to be transduceed to the nucleus
    *Hormonal, metabolic, envrionmental cues → change in TF → Transcriptional regulation
    *Acts is coordination with short-term regulation
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6
Q

What is are the 3 components of energy homeostasis?

A

Balance regulation of fuel
- Intake
- Storage
- Expenditure

Distrubance of energy homeostasis leads to anorexia/obesity → diabetes, heart and kidney failure, fatty liver, cancer

*Metabolic regulation is important for the maintenance of homeostasis

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7
Q

What are the different stages of fatty liver disease?

A
  1. Healthy Liver → fat in < 5% of hepatocytes
  2. MASLD → Steatosis = fat in > 5% of hepatocytes (reversible)
  3. MASH → Steatosis, Inflammation Ballooning, Fibrosis (reversible)
  4. Cirrhosis → Late stages of fibrosis (requires liver transplant, if not, death)
  5. Hepatocellular carcinoma (requires liver transplant, if not, death

*Reversible is not by drugs, but by a change in lifestyle and diet

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8
Q

What is the role, in 2 steps, of transcriptional factors?

A
  1. Receive signal
  2. Bind DNA
    *They don’t necessarily have catalytic activity
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9
Q

What is ChREBP?
How are they Activated?
What pathway do they regulate?

A

ChREBP = Carbohydrate response element binding protein

  • bHLH-leucine zipper transcription factor
  • Phosphorylated by PKA → inactivated (in response to glucagon)
  • Responsive to glucose → Activation by dephosphorylation (PTM) by PP2A (phosphatase)

Regulates glucose and lipid metabolism
*Not responsive to fasting conditions compared to other cases seen

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10
Q

What is FoxO?
How are they Activated?
What pathway do they regulate?

A

Fox O = Forkhead Box Proteins → FoxO1, FoxO3, FoxO4, FoxO6, FoxA2

  • Involved in hepatic glucose production following nutrient deprivation
  • FoxO transcribes gluconeogenesis enzymes
  • Activity is regulated by PTM → phosphorylation and acetylation
  • Insulin → Phosphorylation by AKT → prevents FoxOI to enter the nucleus (no gluconeogenesis in fed state)
  • Glucagon → PKA → indirectly dehosphorylates class II HDAC → activates FoxO
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11
Q

What is CEBP?
How are they Activated?
What pathway do they regulate?

A

CEBP = CCAT-enhancer binding protein (6 different but related proteins)

  • Basic leucine zipper transcription factor
    *Constitutively ACTIVE (still working in low abundance, but not much effect)
  • Signal-independent
  • High expression in the liver → major role in response to fasting
  • Regulated by transcriptional regulation, no PTMs or localization control (in fasting → more transcription of CEBP)

Plays an important role in response to fasting (only time it’s expressed)

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12
Q

What are Nuclear Receptors?
How are they Activated?
What pathway do they regulate?

A

Nuclear receptors → family of 48 ligand-responsive “zinc finger” transcription factors

  • Many members work as “metabolic sensor” involved in all aspects of metabolism
  • Most NRs are directly activated by their ligand
  • Also regulated by PTMs and protein stability
  • Need coregulators, they just bind to DNA, don’t have catalytic activity

*NR act as hubs that have the ability to integrate multiple metabolic signals and control specific metabolic programs
*Coactivators can also integrate multiple metabolic signals anc control speciifc metabolic programs

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13
Q

What are the characteristics of metabolic coregulators?

A

Metabolic coregulatores do not bind DNA
- Respond to metabolic signals
- Interact with TF and/or other coregulators → leading to control of specific metabolic programs

  • Can act as scaffolds to recruit other coregulators or transcription machinery
  • Can posess enzymatic activity → to modulate chromatin accessibility / activity of TF / other coregulators
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14
Q

What are the 2 subtypes of metabolic coregulators?

A

Coactivators and Corepressors

NCOA: nuclear receptor coactivator (also known as SRC, steroid receptor coactivator)
- Family contains 3 members involved in all aspects of metabolism (lipid, carbohydrate, amino acids)

NCOR1 and R: nuclear receptor corepressor
- Coregulators that oppose the action of the NCOAs and other coactivator proteins
- Can also associate with CREB
- Transcriptional effect depends on the tissue

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15
Q

What is PGC-1a?

A

Physiological activator and TF partner

PGC-1a and b → “master” coactivators that interact with multiple TFs
- Most predominantly the nuclear receptors PPARs and ERRs
- Required for mitochondrial biogenesis, oxidative metabolism and heat production by brown fat

Adipose tissue: Glucagon, Cold exposure, Adregenic signalling → cAMP/PKA → PGC-1a activation → bind PPARa/y, ERRa …

Muscle: Exercise → Ca/CAMKII/p38 → PGC-1a activation…

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16
Q

What is the main negative regulator of PGC-1a?

A

KAT2A and B → lysine (K) acetyl transferase
- Also known as GCN5 and PCAF
- Histone acetyltransferases
- KAT2A acetylates PGC-1a → decreases its activity
- Blunts PGC-1a induced gluconeogenesis
*In high energy state

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17
Q

What is the main positive regulator of PGC-1a?

A

SIRT1 → a sirtuin, a NAD+-dependent deacetylase
- Activates PGC-1a to control mitochondrial function
*In energy depletion/low energy state

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18
Q

What class of transcription factors are the target of several drugs that control metabolism?

A

Nuclear Receptors
- Master regulators of metabolism
- Have many small molecule ligands

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19
Q

What are the different superfamilies of nuclear receptors?

A
  1. Classic
  2. Adopted
  3. Foster homes
  4. Orphan
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20
Q

What molecules act as ligands for Classic nuclear receptors?

A
  • Thyroid hormones
  • All-trans-retinoic acid
  • Vitamin D
  • Oestrogens
  • Cortisol
  • Aldosterone
  • Progesterone
  • Androgens
  • DHT
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21
Q

What molecules act as ligands for Adopted nuclear receptors?

A
  • Haem
  • Cholesterol metabolites
  • Bile acids
  • 9-cis-retinoic acid
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22
Q

What molecules act as ligands for Foster homes nuclear receptors?

A
  • Fatty acids
  • Xenobiotics
  • Phospholipids
  • Cholesterol metabolites
    Ex: PIP2, Linoleic acid
    *Sense FA state to regulate synthesis
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23
Q

What molecules act as ligands for Orphan nuclear receptors?
What are these nuclear receptors regulated by?

A

Ligands are not known

The activity of orphan NR is regulated by level of expression, PTMs and protein stability

Drugs binding to the ligand-binding domain of some orphan nuclear receptors have developed suggesting that they are indeed regulated by endogenous ligands, yet to be discovered. Thes ligands are likely to be intracellular metabolites whose levels fluctuate with energy state of the cell.

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24
Q

What are the different functional domains of Nuclear Receptors?

A

*These domains are targeted for post-translational modifications (acetylations, phosphorylation)

  1. NTD-AF1 (bound by NCoA/R, Site of PTMs) → Transactivation (AF-1) + coregulator interaction
  2. DNA-binding-domain → Zinc finger, Dimerization
  3. Hinge
  4. LBD-AF2 (Ligand binding domain, bound by NCoA/R) → Dimerization (homo/hetero), Transactivation (AF-2), Coregulator interaction
  5. CTD

*PTMs can occur anywhere on the nuclear receptor

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25
Q

How do Nuclear Receptors recognize specific DNA sequences near metabolic genes?

A

2 core motifs: AGGTCA and AGAACA

Different nuclear factors recognize variations of that motif:
- Homodimers → Inverted repeat with variating space between both motifs
- Heterodimers → Direct repeats separated by varying spaces
- Monomers → Extended half-site

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26
Q

What are the 2 core motifs recognized by Nuclear receptors on DNA?

A

AGGTCA (TGACCT)
AGAACA (TGTTCT)

*The one in parenthesis is the inverted strand, also recognized
*NRs control all steps in the production of cellular energy from major substrates

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27
Q

What experimental technique allows genome-wide identification of target genes?

A

*Identify what sequences a TF binds to → ChIP-sequencing

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28
Q

What are different genes targeted by ERRa?

A

ERRa = Estrogen-related receptor alpha
- Acadm (MCAD)
- Fh1 (Fumarate hydrates)
- Cs (citrate synthase)
- Sdha (Succinate dehydrogenase)
- G6pc (Glucose-6-phosphatase)
- Pdk4 (pyruvate dehydrogenate kinase)
- Pck1 (PEPCK)
- Pcx (pyruvate carboxylase)
Activates Gluconeogenesis
*Very important in glucose metabolism, TCA, fatty acid oxidation

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29
Q

How do NRs and coactivators regulate specific metabolic programs?

A

They can both integrate multiple metabolic signals to modulate the outcome

30
Q

What does transcriptional regulation of metabolic genes requires?
What type of analysis showed this?

A

Analysis of cistromes of metabolic TFs show that binding of these factors cluster to “hot spots”, regulatory regions, promoters and enhances near metabolic genes that contains sites for several of these factors

Transcritpional regulation of metabolic genes requires the COORDINATED action of several factors

31
Q

What is a superenhancer?

A

It is a collection of enhancers regulating the same gene

32
Q

What is a Cistrome?

A

The set of genomic loci occupied by a particular TF, coregulator or associated with an epigenomic modification
→ Each cistrome is specific to a cell type, tissue, species, physiological state, etc.

*TF cistromes are identified by ChIP-sequencing

33
Q

What are the different ways TF and coregulators can be activated?

A
  • Direct binding of hormones and metabolites
  • Gain or loss of PTMs
  • Protein cleavage
  • Expression levels (signal-independent)
  • Degradation
34
Q

Which gene is mutated as a genetic cause of MODY? (maturity onset diabetes of the young)

A

Nuclear Receptor HNF4a

35
Q

What is the functional structure of of HNF-4a? What is its activation vs inhibition signal?

A

*NR mutated in MODY
- Central zone = surfaces from 2 LBDs, the DBD or the upstream subunit + hinge region of the downstream subunit
- Central zone used by different functional domains of HNF-4a to communicate between each other

Activation signal of HNF-4a:
Metylation of R91 (arginine residue) by coactivator PRMT 1 → glues DBD junctional interface with both LBDs (stable active conformation)

Inhibtion signal of HNF-4a:
Phosphorylation of S78 by PKC creates a clash with Y319 of the LBD (a residue that physically connects the LBD with DBD) → comprises integrity of the fold needed for DNA binding

36
Q

What are the different MODY-linked mutations in HNF-4a?

A
  1. Point mutations in central zone of dimers → MODY I OR hyperinsulineaemic hypoglycemia (not at the same time)
  2. Mutations in the hinge region → misalign 2 DBDs which prevent them ti interact with successive AGGTCA ahlf-sites (DRI)
  3. Many different mutations (ex: I314F and R324H) in the LBD located in the central zone reduce DNA binding affinity (changing the interaction with DBD and HR
  4. No mutation/loss of DBD because this would kill HNF-4a and it is required for liver development (lethal)
    By reducing the activity of HNF-4a → these mutations lead to the development of MODY
    IMPORTANT: Germ-line mutations in TF responsible inherited metabolic diseases demonstrate the biological significance of transcription in the control of hepatic metabolism
37
Q

What is the importance of Bile acid metabolism in general?

A

Bile acids = seroid acids → form micelles to help lipases to digest lipids and bring them near the intestinal brush border membrane for absorption
- Synthesized in the liver from cholesterol
- Can’t diffuse across membranes (→ circulation), need transporters
- Facilitate excretion of lipids and steroids
- Aids in absorption of dietary lipids and vitamins from diet

Enterohepatic circulation: Capture of BA and other steroids produced/metabolized in the liver → secreted to intestine for reabsorption back into circulation and transport back to liver

BA ~ 95% are reabsorbed in ileum → 3-5g being recycle mutliple times/day
~5% of total BA secreted in feces → elimination of cholesterol

38
Q

What are the general steps of the pathway of synthesis of bile acids?
What is the rate-limiting step?

A

BA are synthesized in the liver from cholesterol → series of oxidations by cytochrome p450, Cyp7a1, Cyp7b1 and Cyp27a1

Rate limiting step: Cyp7a1 → initiates the «neutral pathway» → synthesis of cholic acid and CDCA
Cholic acid and CDCA = terminal metabolites → further conjugated to amino acids, glycine and taurine

BA conjugates = amphipatic with one hydrophilic face + one hydrophobic face → easier incorporation into micelles, but prevent their diffusion across membranes
*Transport of BAs requires a specific transporter (ASBT)

39
Q

What is the role of Cyp7a1?

A

It catalyzes the rate-limiting step of Bile acid synthesis from cholesterol:
Cholesterol → {Cyp7a1} → 7a-hydroxycholesterol
*7a-hydroxycholesterol is a ligand for LXR

40
Q

What is the main function of FXR?
What are the ligands of FXR?

A

CDCA and Cholic acid → terminal metabolites of BA synthesis

FXR acts as a BA intracellular sensor: high BAs → FXR - represses synthesis of BAs

Ligands of FXR = Cholic acid & CDCA

Repression of BA synthesis requires FXR action in 2 tissues:
1. Induce FGF15 expression (signaling molecules) in the intestine
2. SHP (NR) in the liver

41
Q

What phenotype is seen in FXR-null mice?

A

Elevated levels of serum Bile Acids, cholesterol and Triacylglycerides due to lack of repression of bile acid synthesis
- Feedback inhibition from CDCA and Cholic acid (end products) → bind to FXR ligand → repress

42
Q

How is Cyp7a1 controlled by cascade of nuclear receptors?

A
  1. FXR does not direclty regulate Cyp7a1 expression: FXR forms heterodimer with RXR → induce expression of SHP with the help of coactivators
  2. SHP forms heterodimer with LRH (another orphan nuclear receptor)
    In low BAs → inactive FXR → SHP (liver) and FGF15 (intestine) not expressed → LRH forms a heterodimer with RXR → associates with coactivators → LRH/RXR dimer positively regulates expression of Cyp7a1

In high BAs → active FXR → SHP (liver) and FGF15 (intestine) are expressed → activates FXR/RXR → signal that dictates corepressor proteins to form complex with LRH/SHP → inhibit expression of Cyp7a1
*SHP and FGF15 inhibit Cyp7a1 and Asbt expression

43
Q

How is ASBT controlled by cascade of signals and of nuclear receptors?

A

Asbt encodes the major BA transport system in ileal enterocytes
- Presence of CDCA (BA end-product) → Shp + FGF15 expression → no production of BAs and transport (ASBT)
- Absence of CDCA → no corepressor complex → coactivator complex binds → production of BAs and transport (ASBT)

44
Q

What is the Bile Acid regulation pathway a good example of?

A

Good example of 2 signals (BAs and FGF15) regulating a cascade of TFs (FXR/RXR > LRH/SHP > LRH/RXR) with a switch between coactivators & corepressors resulting in transcriptional control of bile acid synthesis and transport

45
Q

What is the effect of a defficiency in ASBT?

A

ASBT = Bile acid transport system
Deficiency in ASBT → Bile Acid malabsorption disease

46
Q

Which 3 transcription factors/coregulators are important in regulation of fructose meabolism and the obesity epidemic?

A

SREBP-1c, ChREBP, PGC-1b → Hepatic lipid synthesis

47
Q

What is the problem with High fructose corn syrup? (HFCS)

A

Dietary component found mostly in junk food, but everywhere
Causes Metabolic syndromes → Obesity, diabetes, MASLD, antherosclerosis, cardiometabolic and kidney diseases, cancer, etc.
Fructose is a lpogenic sugar → that activates a lipogenic program by PGC-1β/SREBP1c/ChREBP leading to an increase in fat deposits and, eventually, obesity, fatty liver and associated disorders

*Start to produce in the US it when couldn’t get sugar cane from Cuba
- Considered a harmful macronutrient
- Fructose is metabolized differently than glucose
- Fructose metabolism → other pathways
- Sugar-sweetened beverages are the highest single contributors
- Fructose induces de novo lipogenesis via generation of GA3P

48
Q

How can fructose induce program of lipogenesis?

A
  • Expression of key enzyme → pyruvate dehydrogenase, fatty acid synthase, involved in lipid synthesis → up-regulated by chronic exposure to fructose
    • Promotion of hepatic lipid synthesis by fructose involves the concerted action of 2 TF (SREBP & ChREBP) and 1 coregulator (PGC-1b)
      *What you eat can directly influence TF cascades regulating crucial metabolic pathways and overall health
49
Q

What occurs during fasting response?

A

During fasting:
- Glucose levels decrease
- Pancrease secretes glucagon
- Liver initiates a response to restores homeostasis
Glycogenolysis → Gluconeogenesis → Ketogenesis
*All these metabolic pathways are regulated at the transcriptional level via concerted action of TF from distinct families (each by specific signals and mechanisms)

50
Q

Which 2 hormones are the main signals of fasting?

A

Which are the main Transcription factors invilved in fasting-response cascade?
Signals = Glucagon (from pancreas) and Glucocorticoid (form andrenal glands)
TF = CREB and GR → regulate a series of metabolic pathways by acting as initiators of a transcription factor cascade
Glucagon → CREB // Glucocorticoids → GR
*A simple signal can initiate a cascade of molecular event necessary for the regulation of a series of connected metabolic pathways (ex: Gluconeogenesis, FAO, Ketogenesis)

51
Q

What can be different causes of Desynchrony of the circadian clock?

A
  • Aging
  • Shiftwork
  • Jet travel
  • Obesity
  • Cancer
52
Q

What can be a positive effect of time-restricted feeding?
What experiment showed this effect?

A

Attenuate the adverse metabolic consequences of high-fat and high-fructose diets irrespective of nutritional quality and quantity by re-setting the clock

Light-restricted feeding in mice (nocturnal animals, reverse feeding) → decreased energy expenditure, decreased CKB expression, decreased creatine synthesis, increased weight gain
Dark-restricted feeding in mice (nocturnal animals, normal feeding) → increased energy expenditure, increased CKB expression, increased creatine synthesis, decreased weight gain

53
Q

What is one of the best ways to set a very stringent circadian clock?

A

By being strict about eat schedule → eat at 10AM and 6PM
Eating = strong clock regulator

54
Q

What is the master clock of the body? What does it directly control?

A

Master clock → in the suprachiasmatic nuclei (SCN), synchronizes peripheral clocks by:
1. Controlling rhythmic signals such as hormones and metabolites
2. Imposing feeding/fasting and body temperature rhythms
The SCN is synchronized by the dark/light cycle and external stimuli

Signal from the master clock are interpreted by immediate early genes conveying information to the central clock controlled genes (CCC) or direclty to output genes (CCC-OG)
Then, Core clock genes regulate the expression of «local clock-controlled» ouput genes (LCC-OG)
- Output genes (OG) are mostly metabolic genes

55
Q

What are the main core clock genes?

A

Bmal1/Clock, Cry/Per, Rev-erb a/b, RORa/b/y

*ALL clocks are composed of the same core clock genes regulated differently

56
Q

When are the levels of Bmal1 the lowest?

A

Highest from midnight - 6AM
Lowest from 12PM - 6PM
*controlled by the master clock/light/dark cycle

57
Q

What is the importance of the metabolite NAD+?

A
  1. It controls SIRT1 activity
  2. SIRT1 is a critical regulator of both the «core clock» (Bmal1, Per2) and the adaptative clock (nuclear receptor and their coregulators)
58
Q

Which proteins are increased/decrease in high BAs?

A

*Goal = stop BA production
- Increased SHP
- Decreased ASBT
- Decrease Cyp7a1

59
Q

Which metabolic TFs are considered as “first responders” in activation of gluconeogenesis?

A

CREB
Glucagon → cAMP → PKA → activation of CREB by phosphorylation

60
Q

What does ChIPseq allows us to do?
What are the steps?

A

Allows to determine the Cistrome of TF in that given condition
1. Extract DNA from cell of interest (coated in different proteins)
2. Cross-link proteins to DNA
3. Shear DNA
4. Ab against protein of interest (not against DNA)
5. Isolate DNA fragments with Ab bound by specific protein receptor
6. DNA amplification
7. DNA sequencing
8. Align to reference genome → big peak where enhancer for specific gene is

61
Q

Which mutations are known to cause MODY vs hyperinsulinemic hyperglycemia?

A

HNF-4a = Nuclear receptor crucial for pancreatic b-cell function and hepatic glucose metabolism

  1. Mutation in HNF-4a which DECREASES its activity → MODY (no insulin secretion)
  2. Mutation in HNF-4a which INCREASES its activity → hyperinsulinemic hyperglycemia

*Both are point mutations in the central zone of HNF-4a dimers

62
Q

Which proteins increase/decrease in low BA conditions?

A

Goal = Increase BA production
- Increased ASBT
- Increased Cyp7A1

63
Q

Explain the metabolite feedback mechanism of the UNIVERSAL core clock.
What are the activator/repressor loops?

A
  1. Bmal1/Clock → bind E-box → transcription of Cry/Per (co-repressors)
  2. Cry/Per accumulate overtime → repress Bmal1/Clock transcription
  3. Eventually, Bmal1/Clock is gone so not more transcription of Cry/Per → they become unstable and degrade → no more repression of Bmal1/Clock
  4. Bmal1/Clock transcription starts again (rhythmicity)
    *Negative feedback loops

Activator loop = Bmal/Clock, RORa/b/y
Repressor loop = Cry/Per and Rev-erb a/b

All core clock genes are TFs, and the circadian clock controls physiologic and metabolic homeostasis through transcription
Clock genes are controlled by NRs translating metabolic signals (eating/sleeping habits), they also control many core clock genes and output genes
→ Transcription factors control the «adaptative clock» and the circadian metabolism

64
Q

What are Immediate Early Genes?

A
  • Rapidly interprets signal from the central clock
  • Allows for quick adaptation to external cues while also synchronizing the tissue’s clock
65
Q

What are Central/Core Controlled OUTPUT genes?

A
  • Genes regulated by SCN
  • Help maintain rhythmic expression of genes systematically
    *Different in all tissues

Ex: G6Pase during fasting

66
Q

What are Local clock controlled OUPUT genes

A
  • Regulated by local clock in tissue (focused on tissue’s role)
  • Tissue specific
    Ex: Cyp7a1 is not expressed in muscle because muscle does not produce bile
67
Q

How does the ADAPTATIVE clock regulate the core clock’s metabolite feedback mechanism?

A

Adaptive clock = lots of NRs as they are bound by their ligands → hormones which sense the external state

NRs + ligand activate transcription of Rev-erba/b → binds to RORElement → decreases/inactivates transcription of Bmal1/Clock

NRs + ligand activate transcription of RORa/b/y → binds RORE → activates transcription of Bmal1/Clock

68
Q

How is SIRT1 related to the circadian rhythm?

A

NAD+ levels vary depending on energy state

Exercise/fasting → high NAD+ → activation of SIRT1 → activation of PGC-1a → Transcription of Bmal1 →… → NAMPT (regulator of NAD → feedback loop)

SIRT1 is also involved in other pathways such as triglyceride/cholesterol homeostasis, Hepatic glucose homeostasis, WAT lipid mobilization

69
Q

What would be the impact of a mutation in FXR preventing it to dimerize with RXR?

A
  • Increase ASBT
  • Increase Cyp7a1 levels → breakdown of cholesterol → lower cholesterol levels
  • Increase in Bile Acids
70
Q

Which receptor is NOT a serpentine receptor?
A) Leptin receptor
B) Glucagon receptor
C) a-adrenergic receptor
D) Ghrelin receptor

A

A) Leptin receptor

71
Q

A germ-line mutation in the gene encoding a TF (HNF-4⍺) is linked to a metabolic disease (MODY).This finding provided genetic evidence that…

A
  1. Transcriptional regulation plays a crucial role in maintaining metabolic homeostasis
  2. co-regulators and PTMs are molecular mechanisms through which metabolic TFs are regulated

BIOC 311 (14 decks)

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