hi

• 1. Allosteric - control of key enzyme activity in metabolic pathway
• 2. Post-translational modification - covalent; p'ation/dep'lation, glycosylation, etc (short term)
• 3. Transcriptional regulation affects LEVELS of key enzymes (longterm regulation)

AMPK activates glucose uptake, glycolysis, FA oxidation, and mitochondrial biogenesis 

AMPK inhibits glycogen/glucose (GNG)/cholesterol/FA/protein synthesis as well as mTOR. 

ACC and FAS

Reduces amount of malonyl CoA, relieving block on CPT1 to allow FA oxidation

• Hypothalamus - food intake
• Skeletal muscle/Heart - FA oxidation, glucose uptake, glycolysis, mitobiogenesis

Liver: Inhibits FA synthesis, cholesterol synthesis, GNG.

White adipose - FA synthesis

Pancreatic B-cells: inhibits insulin secretion.

• 1. Inhibits hepatic GNG (decreases hepatic glucose)
• 2. Increases glucose uptake (muscle; decreases plasma glucose)
• 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. 

In hypothalamus, AMPK simulates neuropeptides that increase feeding behavior during fasting state to maintain whole body energy homeostasis. 

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. 

• 1. Cholesterol
• 2. Insulin:glucagon
• 3. FAs

Both (can regulate long-term by turning on/off multiple genes at once).

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). 

SREBP 1: FAs, TAGs, PLP (FAS, ACC, GPAT)

SREBP 2: cholesterol, LDL-R (HMG CoA Reductase/Synthase)

• 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. 

SRE in promoter region. 

• 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. 

SCAP - SREBP cleavage activating protein that escorts SREBP and senses sterol levels. 

• 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. 

• 1. Increases transcription of HMG CoA Reductase & most other enzymes in chol syn pathway
• 2. Glucose 6 phosphate dehydrogenase (HMP shunt --> NADPH)
• 3. LDL receptor synthesis increases

Activated by insulin

Inhibted by PUFA

• 1. Glucocorticoids (cortisol)
• 2. Mineralocorticoids
• 3. Progesterone
• 4. Aldosterone
• 5. Estrogen
• 6. RAR - all trans retinoic acid
• 7. TR - thyroid hormone
• 8. VDR (1,25-OH vitamin D3)

• 1. RXR - 7 cis retinoic acid
• 2. PPARa 3. PPARB/d 4. PPAR gamma - fatty acids, eicosanoids.

Def: proteins located in cytosol/nucleus that bind to steroid hormones and stimulate/suppress transcription of specific genes.

Domains: DNA binding domain, hormone binding domain (ligand), modulating domain (cofactor binding/plation/deplation), and protein-protein binding domain (dimerization). 

• 1. Enter: Hormones/ligands enter cells or are synthesized in cell
• 2. Bind to Ligand binding domain: Hormones/ligands bind to ligand binding domain of specific receptor
• 3. Activation: Binding causes receptor --> conformational change, activating receptor
• 4. Dimerization: Activated receptor-hormone/ligand complex pairs with another receptor-hormone complex 
• 5. Binding to HRE - DNA binding domain of dimerized receptor hormone complex binds to specific hormone respones element on DNA.
• 6. Stimulates/Suppresses - binding of dimerized RHC upstream of specific genes stimulates/suppresses transcription
• 7. Changes in mRNA expression of different genes alters the abundance of the proteins they encode (enzymes, hormone receptors, etc) leading to changes in metabolism. 

Peroxisomes = subcellular organelles that oxidize very long chain FAs and form/metabolize H2O2

NSAIDS/Fibrates

By activating a transcription factor (PPAR a, g, b,d)

Ligands - PUFAs and eicosanoids (FAs)

• 1. PPAR forms heterodimer with RXR (Retinoid X receptor binds 9-cis retinoic acid)
• 2. Dimer binds to PPRE (peroxisome proliferation response element) in promoters of target genes. 

PPARa - increases trasncription of genes involved in B-oxidation in peroxisomes and mitochondria. So FAs can actually upregulate their own oxidation.

PPAR b/d - same but in skeletal muscle to increase B-oxidationg enes. 

PPARa - accumulate TAGs in liver. (unable to oxidize FAs for energy so it accumulates)


PPAR g - in utero death of PPARg knockout mice. PPARg is vital for preadipocyte differentiation into mature adipocytes (leptin, receptors

• 1. Req for preadipocytes to differentiate into adipocytes.
• 2. Ligands: PUFA, eicosanoids, TZDs (diabetes drugs)

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. 

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.