1. Nutrient Control of Genes

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)

• 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

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. 

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. 

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.

• 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

• 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.

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. 

Senses low cholesterol in ER membrane. 

If senses low amounts, transport vesicle will move from ER to Golgi where it is cleaved twice.

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. 

• (1) SCAP 
• (2) Level of sterols in ER membrane - specifically, amount of bHLH-zip in nucleus

• (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

• 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.

• 1. Increases FA/TAG synthesis
• 2. Activates genes encoding ACC, FAS, GPAT

Activated by insulin. Inhibited by PUFAs. 

• 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. 

• 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. 

NO. 

• 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). 

• 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. 

• 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). 

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.

Because PPAR-a is essential in B-oxidation. W/o oxidation of these FAs, there will be a buildup of TAGs in the liver.

FAs (eicosanoids and PUFAs) serve as the ligands for PPAR-a, which activates B-oxidation in peroxisomes and in mitochondria. 

• 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

• 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

 

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.

• 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.

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. 

Liver, kidney, intestine, adipose tissue.

Essentially tissues involved in TAG synthesis. Works with SREBP-1.

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)

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).

- Glucagon.

• 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.