3. Increases B-oxidation of FAs, decreasing TAG stores --> (1) less lipid intermediates blocking insulin signaling pathway (2) Less inflammatory cytokines released that interfere with insulin signaling.
How does AMPK regulate food intake?
In hypothalamus, AMPK simulates neuropeptides that increase feeding behavior during fasting state to maintain whole body energy homeostasis.
What activates mTOR? (3) What inhibits mTOR (2) What does mTOR lead to? (2) What does inhibition of mTOR lead to?
Activated by growth factors (insulin), amino acids, energy
Inhibited by stress and rapamycin
Leads to cell proliferation/cell growth (why targeted in cancer).
Inhibition of mTOR leads to autophagy.
What are the 3 main nutrients/hormones that control gene expression? 3
Can transcription factors regulate acutely? long-term?
Both (can regulate long-term by turning on/off multiple genes at once).
What are the 4 types of gene regulation?
1. Transcription factor modified by p'lation of dep'lation (regulated by glucose, glucagon, insulin, etc & long-term fasting by high fat/CHO/calorie diet
2. SREBP - bHLHzip (no ligands)
3. Steroid hormone super family: zinc fingers, have small molecule ligands like estrogen and VDR.
4. Epigenetics (methylation or permanent up or down regulation of gene expression).
What is SREBP 1 responsible for? (3 substrates; 3 enzymes)
SREBP2? (2 substrates; 2 enzymes)
SREBP 1: FAs, TAGs, PLP (FAS, ACC, GPAT)
SREBP 2: cholesterol, LDL-R (HMG CoA Reductase/Synthase)
How does SREBP transform from precursor protein to entering the nucleus? 4
1. Synthesized as precursor protein w/ 2 transmembrane domains
2. Site 1 protease (S1P) cleaves amino and carboxylic parts off of SREBP
3. S2P THEN cleaves at cytosolic side and releases bHLH-zip amino terminus domain. -->
4. bHLH-Zip enteres nucleus.
What specific nucleotide sequences does HLH of SREBP interact with?
SRE in promoter region.
How does SREBP respond to low serum cholesterol? 4
1. Low serum LDL chol = less chol in cell
2. Activates SREBP 2
3. SREBP 2 activates synthesis of cholesterol and LDLR
4. Increased LDL-R brings more chol into cell and lowers serum cholesterol.
What regulates SREBP? 1 Functions (2)
SCAP - SREBP cleavage activating protein that escorts SREBP and senses sterol levels.
What happens with SCAP and SREBP in high sterol levels? (2) Where from? (1) Where to? (1) In low sterol levels? (2)
High sterol levels:
- SCAP and SREBP interact & SCAP/SREBP complex does NOT enter transport vesicles (stays in ER).
Low sterol levels:
- SCAP & SREBP complex enter transport vesicles
- Go to golgi where Site1and Site 2 proteases live.
What are functions of SREBP 2 on enzymes and substrates? (3)
1. Increases transcription of HMG CoA Reductase & most other enzymes in chol syn pathway
3. 1. Increase glucose uptake/use by skeletal muscle (2) Decrease GNG and glucose output (3) Decrease TAG syn in liver. (4) No effect on insulin (5) Increase transcription of cholesterol transporter in foam cells and promote cholesterol efflux. (6) Decrease cytokine production.
How do TZDs increase insulin sensitivity? (2)
1. TZDs decrease stored TAG in liver/muscle (released FAs goes to fat cells for storage, the resulting decrease in the amount of lipid stored in liver/muscle increases insulin sensitivity in these tissues.
2. TZDs act directly on fat cell - increase glucose transporters and promote fat storage. Decrease FA release, decrease fat-cell derived cytokines (e.g. TNFa) that cause insulin resistance in liver/muscle.