1. Nutrient Control of Genes
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What does AMPK generally regulate? 2 What are its main functions? (3) What are its specific functions?
AMPK regulates both cell and whole body energy homeostasis.
- Main function: (1) inhibits energy consuming pathways (FA/TAG/cholesterol/glycogen synthesis)
- (2) Increases oxidative pathways to increase ATP (glucose uptake, glycolysis, B-oxidation, mitochondrila biogenesis)
- (3) Key modulator of lipid metabolism: For example, inhibits FA synthesis in liver, skeletal muscle, and hypothalamus: Inhibits ACC --> reduces MaCoA substrates for FA synthesis, while decreasing block on CPT-1, enhancing B-oxidation. Also, inhibits FAS expression!! (2)
What does AMPK do in the following tissues?
Skeletal muscle/heart (4)
White adipose (1)
Pancreatic B-cell (1)
- Hypothalamus - increases food intake.
- Skeletal muscle/heart - Glucose uptake, glycolysis, FA oxidation, mitochondrial biogenesis.
- Liver - blocks FA synthesis, cholesterol synthesis and gluconeogenesis.
- White adipose - blocks FA synthesis
- Pancreatic B-cell - blocks insulin secretion
How does leptin affect AMPK? Where (2)? To do what? How? (3) What does it do in liver? What drug mimics leptin in this way?
Leptin activates AMPK in skeletal muscle/periphery to maintain insulin sensitivity by inhibiting FA synthesis, stimulating FA oxidation (via inhibition of ACC and activation of PPARa) & stimulates glucose uptake.
Decreases hepatic GNG.
What does Metformin do? 3
How does it activate this specific molecule?
Metformin - (1) reduces plasma lipid levels bc of increased B-oxidation, (2) increases insulin sensitivity in liver/muscle by increasing glucose uptake/glycolysis/FA oxidation & (3) reducing TAG stores.
Mildly inhibits complex 1 of ETC --> increases AMP:ATP ratio, activating AMPK.
What stimulates mTOR? (3) What inhibits it? (2) What does it lead to? (2). What is an important role of stopping mTOR?
mTOR is stimulated by growth factors (i.e., insulin), AAs, energy. Inhibited by stress/rapamycin
Leads to cell growth and proliferation
Autophagy - induction (external stimuli), autophagosome formation, docking & infusion, breakdown of autophagic vesicle.
What are the five types of gene regulation? (5)
- 1. Transcription factor modified by p'lation/dep'lation AND long-term regulation by fasting, high CHO, high fat diets
- 2. SREBP
- 3. ChREBP
- 4. Steroid hormone super family
- 5. Epigenetics
- What does it stand for?
- What molecules does SREBP 1 control? (3) Enzymes? (3)
- What molecules does SREBP 2 control? (2) Enzymes (2)
- Structure? What does this structure allow for?
- SREBP: Sterol Regulatory Element Binding Protein
- SREBP 1: Controls FAs, PLs, TAGs (FA synthase, ACC, TAG enzymes)
- SREBP2: Cholesterol & LDL-R (HMG CoA Reductase & HMG CoA Synthase).
Structure: Helix-loop-helix leucine zipper - allows protein to coil around DNA.
How is SREBP-2 initially synthesized? What is it bound to?
What does it require to activate it? (3) Where does it go once its activated? What does it interact with in what region? What does it influence?
Precursor protein with 2 transmembrane domains bound to SCAP (SREBP cleavage activating protein).
(1) requires SCAP to sense low cholesterol levels. (2) Low sterol levels transport SCAP-SREBP from ER to Golgi (3) In Golgi requires 2 protein cleavages to release bHLH-zip domain from membrane (Site 1 protease - S1P releases amino & carboxylic parts of SREBP). S2P cleaves at cytosolic side and releases bHLH-zip amino terminus domain.
bHLH-zip domain enters nucleus and interacts with SRE (SREBP-2) (sterol regulatory element) on the promoter region of the gene.
Influences mRNA for LDL-reductase, HMG CoA reductase & synthase.
What is SCAP's role? What happens if it senses low amounts of stuff?
Senses low cholesterol in ER membrane.
If senses low amounts, transport vesicle will move from ER to Golgi where it is cleaved twice.
What happens to SREBP transport if there are high levels of sterols? (2)
High sterols inhibit ER-Golgi transport of SREBP by inducing conformational changes in two chaperones: SCAP (transport protein) and INSIG (ER anchor protein).
Binding of sterols to either of these makes SCAP and INSIG stay bound, so SCAP can't enter ER-Golgi transport vesicles. High sterol levels bind to INSIG --> ubiquitination & protesasomal degradation of reductase.
How is SREBP regulated? (2)
- (1) SCAP
- (2) Level of sterols in ER membrane - specifically, amount of bHLH-zip in nucleus
What are the functions of SREBP-2? (3)
- (1) Increases Tx of HMG-CoA reductase & most other enzymes in cholesterol synthesis pathway.
- (2) Increases Tx of Glucose 6 P dehydrogenase (HPM shunt --> NADPH)
- (3) Increases Tx of LDL-receptors
What happens if there is a net result of low cholesterol in the ER or a statin drug?
What happens to cell cholesterol? What happens to serum cholesterol?
- 1. Activation of SCAP, allowing ER-golgi transport of SREBP
- 2. SREBP binds to SRE, activating target genes and Tx
- 3. Increased synthesis of cholesterol
- 4. Increased LDL-R mediated entry of LDL-cholesterol.
Cell cholesterol increases a lot, while serum cholesterol decresaes a lot.
What is the function of SREBP-1? What genes does it activate?
Activated by? (1) Inhibited by? (1)
- 1. Increases FA/TAG synthesis
- 2. Activates genes encoding ACC, FAS, GPAT
Activated by insulin. Inhibited by PUFAs.
What would you expect if SREBP-1 was upregulated in liver> If it were inhibited? If you ate a meal high in omega 3s, what would happen to hepatic syn of TAGs?
- 1. If upregulated in liver, would see increase in FA synthesis and TAG synthesis in liver --> fatty tissue and increased VLDL.
- 2. If it were inhibited, liver could process more fats returned to liver from blood, decreasing plasma lipid levels.
- 3. A meal high in omega 3s would decrease hepatic syn of TAGs.
What makes a molecule part of the steroid R super family? Is SREBP 1/2 part of this family?
- 1. Receptors bind to hormones and undergo structural change.
- 2. Steroid receptor pairs up with ANOTHER receptr-hormone complex (dimerization) - can be identical or different (homodimer or heterodimer)
- 3. The dimerized receptor-hormone complex binds toa specific sequence on DNA called hormone or whatever else response element.
What are the four domains of a steroid hormone receptor?
- 1. DNA binding domain
- 2. Hormone binding domain (ligand)
- 3. Modulating domain (cofactor binding, p'lation, dep'lation)
- 4. Protein-protein binding domain (how steroid receptors dimerize).
What is the mechanism of action for hormones? 7 steps
- 1. Hormones or ligands enter cell (or are synthesized in cell)
- 2. Hormones bind to ligand binding domain of specific receptor
- 3. Binding causes structural change in receptor --> activation
- 4. The activated receptor-hormone complex pairs up with another receptor-hormone compelx (dimerization)
- 5. The DNA binding domain of the dimerized receptor-hormone complex binds to a specific sequence on DNA called the hormone respones element
- 6. Binding of dimerized receptor-hormone complex upstream of specific genes either stimulates/suppresses transcription.
- 7. Changes in mRNA expression alters abundance of proteins they encode, leading to changes in metabolism.
What does PPAR stand for?
What are ligands for PPARs? Are they exogenous or endogenous?
- Peroxisome proliferator activator receptor.
- Peroxisome - subcellular organelles that form/metabolize H2O2 and perform B-oxidation of very long chain FAs.
Ligands: eicosanoids and PUFAs (endogenous).
What is PPAR-a? Function of PPARa?4 - what is its ligand?
PPAR-a is a tx factor and a major regulator of lipid metabolism. It is activated under nutrient-def conditions and is necessary for ketogenesis. Also promotes uptake, utilization, and catabolism of FAs by increasing Tx of genes involved in B-oxidation in peroxisomes & mitochondria.
Ligand = FAs, so they upregulate their own oxidation.
PPARb/d do the same thing as ppar-a, but particularly in skeletal muscle to increase B-oxidation genes.
Why do PPAR-a knockout mice accumulate TAGs in liver?
Because PPAR-a is essential in B-oxidation. W/o oxidation of these FAs, there will be a buildup of TAGs in the liver.
How do FAs upregulate their own oxidation?
FAs (eicosanoids and PUFAs) serve as the ligands for PPAR-a, which activates B-oxidation in peroxisomes and in mitochondria.
What is the mechanism of action for PPAR-a? (2)
What is PPARgamma important for? (4)
What are ligands for PPARg? (3)
- 1. FAs enter liver and bind to PPAR-a
- 2. PPAR-a & FA complex bind to DNA and activate RNA polymerase for CPT-1, ACS, and other FA oxidation enzymes.
PPARgamma is requird for adipocyte differentiation: mRNA for leptin, LPL, FA transporters.
Ligands: PUFA, eicosanoids, and TZDs
What do TZD drugs treat? What do they increase? How? (3)
How do they influence insulin secretion? - 1
How do they combat atherosclerosis? - 2
- Diabetes. They increase insulin sensitivity.
- (1) Increase glucose uptake/use by skeletal muscle
- (2) Decrease GNG and glucose output
- (3) Decrease TAG synthesis by liver
- (4) No effect on insulin secretion
- (5) Increase tx of cholesterol transporter in foam cells and promote cholesterol efflux
- (6) Decrease cytokine production
How do TZDs affect preadipocytes? How does this help with insulin senstivity/atherosclerosis? - 2 hypotheses
They induce preadipocytes to differentiate into adipocytes.
- Hypothesis 1: TZDs decrease stored TAG in liver and muscle
- - Released FA goes to fat cells for storage
- - Resulting decrease in amount of lipid stored in liver & muscle increases insulin sensitivity in those tissues.
- Hypothesis 2: TZDs act directly on fat cells
- - Increase glucose transporters and promote fat storage
- - Decrease FA release
- - Decreased fat cell-derived cytokines (e.g. TNF-a) that cause insulin resistance in liver & muscle.
What does ChREBP stand for? What is it mainly responsible for? How does glucose --> fat synthesis? 2
- ChREBP - Carb response element binding protein.
- Responsible for why eating a high carb diet makes you fat.
- Glucose --> G6P --> glycolysis --> pyruvate --> acetyl CoA
- Glucose ---> PPP shunt to make NADPH.
- Acetyl CoA + NADPH = FAT SYNTHESIS.
What does ChREBP behave like? What are the similarities? How does it behave like its friend?
Like SREBP-1 - bc it upregulates the same enzymes (ACC, FAS, GPAT)
Insulin (rises with high CHO) stimulates SREBP-1 which increases FAS, ACC, GPAT
Glucose increases ChREBP (rises with high CHO) in TAG synthesis tissues (liver, kidney, intestine, adipose).
Basically, both are stimulated by a high carb meal.
Where is ChREBP located?
Liver, kidney, intestine, adipose tissue.
Essentially tissues involved in TAG synthesis. Works with SREBP-1.
What is ChREBP's mechanism of action? What is its structure?
Structure: helix-loop-helix leucine zipper bHLH-zip
Binds to carbohydrate response element on the promoters of genes that encode lipogenic enzymes (ACC, FAS, GPAT)
How is ChREBP regulated? (4) What is its active form?
What is PUFAs role? (2)
Active form - dephosphorylated form (pattern of insulin)
- 1. mRNA of ChREBP is upregulated by insulin, glucose, and TZDs.
- 2. Downregulated by FAs.
- 3. Fasting followed by refeeding with high CHO diet --> 10fold increase in ChREBP mRNA in adipose tissue.
- 4. Glucose6P promotes dephosphorylation of ChREBP (and its activation)
- 5. PUFAs inhibit ChREBP activity by (1) increasing decay of ChREBP mRNA (2) decreasing ChREBP translocation from cytosol to nucleus (PUFAs inhibit glycolytic enzyme activity ---> results in decreased glucose metabolites).
What hormone initiated pathway do you think would phosphorylate and inactivate ChREBP?
What is the role of PUFAs in gene transcription? (4)
- 1. Inhibit ChREBP activity by increasing decay of its mRNA and to decrease ChREBP translocation from cytosol to nucleus.
- 2. PUFAs inhibit glycolytic enzyme activity --> decreased glucose metabolites.
- 3. Inhibit SREBP-1 (fat synthesis)
- 4. Serve as ligands for PPARs, which activates B-oxidation in peroxisomes and mitochondria.
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