Hormonal Regulation Flashcards
What different factors are considered in transcriptional control ?
- 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 - The molecular MECHANISM by which transcription factors regulate gene expression
- Ex: Recruitment of coregulators, corporation with other TF, etc.) - 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
What is CREB?
What are its family members?
How are they Activated?
What pathway do they regulate
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
What is SREBP-1c?
How are they Activated?
What pathway do they regulate
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)
- Signal (inside) → Sterols keep SCAP-SREBP in the ER bound to Insig
- Activation → In the Golgi, S1P cleaves SREBP
- Transcription → S2P cleaves bHLH → goes to the nucleus → Lipogenesis
What mechanisms are involved in short-term regulation or metabolic pathways?
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
What mechanisms are involved in long-term regulation of metabolic pathways?
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
*Hormonal, metabolic, envrionmental cues → change in TF → Transcriptional regulation
*Acts is coordination with short-term regulation
What is are the 3 components of energy homeostasis?
Balance regulation of fuel
- Intake
- Storage
- Expenditure
Distrubance of energy homeostasis leads to anorexia/obesity → diabetes, heart and kidney failure, fatty liver, cancer
What are the different stages of fatty liver disease?
- Healthy Liver → fat in < 5% of hepatocytes
- MASLD → Steatosis = fat in > 5% of hepatocytes (reversible)
- MASH → Steatosis, Inflammation Ballooning, Fibrosis (reversible)
- Cirrhosis → Late stages of fibrosis (requires liver transplant, if not, death)
- Hepatocellular carcinoma (requires liver transplant, if not, death
*Reversible is not by drugs, but by a change in lifestyle and diet
What is the role, in 2 steps, of transcriptional factors?
- Receive signal
- Bind DNA
*They don’t necessarily have catalytic activity
What is ChREBP?
How are they Activated?
What pathway do they regulate?
ChREBP = Carbohydrate response element binding protein
- bHLH-leucine zipper transcription factor
- Phosphorylated by PKA → inactivated
- Responsive to glucose
- Activation by removal of the phosphate (PTM) groups by PP2A (phosphatase)
Regulates glucose and lipid metabolism
What is FoxO?
How are they Activated?
What pathway do they regulate?
Fox O = Forkhead Box Proteins → FoxO1, FoxO3, FoxO4, FoxO6, FoxA2
- Involved in hepatic glucose production following nutrient deprivation
- Activity is regulated by PTM → phosphorylation and acetylation
- Phosphorylation by AKT in response to insulin signalling prevents FoxOI to enter the nucleus (no gluconeogenesis in fed state)
What is CEBP?
How are they Activated?
What pathway do they regulate?
CEBP = CCAT-enhancer binding protein (6 different but related proteins)
- Basic leucine zipper transcription factor
- Constitutive activity
- 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)
What are Nuclear Receptors?
How are they Activated?
What pathway do they regulate?
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
What are the characteristics of metabolic coregulators?
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
What are the 2 subtypes of metabolic coregulators?
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
What is PGC-a1?
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…
