Exam #2 TAG synthesis

• In liver, it is packed in VLDL to delivery endogenously derived lipids around body.
• In adipose tissue, it is stored. 

Phospholipids

• 1. Ep/glucagon bind to 7-transmembrane G-protein coupled receptor. G protein activates adenylate cyclase: ATP--> cAMP. cAMP activates PKA.
• 2. PKA phosphorylates and activates Hormone Sensitive Lipase which activates ATGL (adipocyte TG lipase) to cleave off FAs (1st and/or 3rd) leaving MAG.
• 3. MAG lipase hydrolyzes MAG to free glycerol and 3 FAs. 
• 4. Glycerol --> liver for GNG
• 5. FAs --> acetyl CoA for TCA cycle for energy.
• 

• 1. Insulin binds to receptor activating phosphatase that d'plates and deactivates HSL. Decreases lipolysis
• 2. Also activates phosphodiesterase that breaks down cAMP stopping cAMP secondary pathway. Decreases lipolysis
• 3. Increases glucose entry (GLUT 4) for glycerol backbone
• 4. Increases FA entry from lipoproteins by increasing lipoprotein lipase activity. Insulin activates ApoCII which activates LPL to cleave off FAs for uptake into body. 

• LPL is synthesized and secreted by fat, heart, and skeletal muscle.
• It's main function is to increase FA entry into cells via lipolysis from TAGs
• Activated by ApoCII which is activated by insulin. 

• 1. Diffuse through cell membrane and travel with albumin through blood.
• 2. Transported to tissues, enter cells
• 3. Activation by acyl CoA synthetase
• 4. Oxidized for energy in mitochondria OR re-esterified (over 50% of FAs are re-esterified). 

• 1. Glycerol cannot return to adipocytes (no glycerl kinase) so goes to liver for phosphorylation/activation.
• 2. Can form TAG 
• 3. Or can form DHAP for glycolysis or GNG. 

TAG, glucose, or undergo DHAP for TCA cycle

Since ATGL (acyl TAG lipase) is essential for TAG hydrolysis, you wouldn't be able to properly lipolize your TAGs into glycerl and FAs leading to accumulation of TAGs in bad places (i.e. heart)

Knockout mouse. 

Yes, once it's phosphorylated it moves from the cytosol to the surfaces of the lipid droplets!

In basal lipolysis, ATGL is located partially to the LD and HSL in cytoplasm. Rate of lipolysis is VERY low --> released FAs are resynthesized back into lipid (futile cycling) or directed toward oxidation in mitochondria. 

Proteins

Pancreatic lipase and colipase in gut lumen

Adipose tissue does not have glycerol kinase, so cannot process free glycerol.

Because needs substrate for backbone of TAG (glycerol) which is a product of glycolysis and cannot use free glycerol.

It's called lipodystrophy. No, because adipose tissue secretes hormones such as estrogen, adiponectin and leptin. Adiponectin is important (higher levels) for protecting against metabolic derangements. Leptin = satiety factor. Person will be constantly hungry and with no adipocytes, extra energy will be stored in bad places ilke the heart!

Like ATGL deficiency.

Inject leptin (peptide hormone)

• 1. Acyl CoA synthetase: FA + ATP + CoA --> FA CoA
• 2. Carnitine palmitoyl transferase 1 (CPT1) combines fatty acyl CoA and carnitine to form acylcarnitine + CoA (plucks off CoA).
• 3. Acylcarnitine enters mtitochondria via carnitine-FA transporter. 

• 4. CPT2: Acyl carnitine --> FaCoA (carnitine is released, recycled and exits via carnitine-FA transporter).
• 5. FaCoA undergoes B-oxidation. Final product: acetyl CoA, NADH, FADH2

Mit matrix

Carnitine-FA transporter

• 1. Malonyl CoA (from ACC - FA synthesis) inhibits CPT1 (Low insulin:glucagon inhibits ACC, inhibiting malonyl CoA production, so CPT1 is free). 
• 2. Magnitude of lipolysis (based on low insulin:glucagon/ep/ACTH) how many FAs have been released
• 3. CPT-1 and entry of acyl CoA into mitochondria (this entire transport system is the major regulated step!)
• 4. AMPK - signals low energy, inhibits anabolic pathways, inhibits ACC --> less maCoA and more CPT1.
• 5. PPARalpha - nuclear transcription factor whose synthesis is increased by cortisol (during fast). Works like steroid hormone, interacts w/ CPT1 gene promoter and enhances gene expression of B-oxidation enzymes including CPT1. 

Syn of FAs, TAGs, and cholesterol

Synthesized in liver and kidney from lysine and methionine. From diet. 

Not common - if there is a deficiency, generally genetic. 

• 1. Supplies GNG with ATP and NADH (directs pyruvate/lactate away from oxidation towards glucose synthesis by inhibiting PDH!)
• 2. Provides ketone bodies for peripheral tissues
• 3. Spares protein degradation during fasting/starvation
• 4. Spares glucose use in peripheral tissues

GNG would most likely be impaired leading to hypoglycemia. 

• 1. Fatty acid splits into acetyl CoA (TCA) and acetoacetyl CoA (substrate for ketone body syn).
• 2. HMG CoA synthase: acetoacetylCoA --> HMG CoA
• 3. HMG CoA lyase: splits HMG CoA back into acetyl COA and acetoacetate (basically to get rid of CoA). 
• 4. Acetoacetate can spontaneously convert to acetone or turn into B-hydroxybutyrate (Carboxylic acid) via b-hydroxybutyrate dehydrogenase. 

• 

• (C-2)/2 NADH and FADH2 (5 ATP total). 
• 12 ATP for each acetyl CoA (C/2*12)

-2 ATP needed for activation of palmitate to palmitoyl CoA>

• 1. Starvation or low CHO diet.
• 2. Liver
• 3. Acetone, acetoacetate, B-hydroxybutyrate

• 1. PRovide energy fuel from TAG to brain/peripheral tissues
• 2. Reduce/conserve glucose use
• 3. Prevent excess loss of skeletal protein for GNG

many are like FA functions. 

• 1. Liver is flooded with FAs mobilized from adipocytes
• 2. Resulting elevated hepatic acetyl CoA inhibits PDH and activates pyruvate carboxylase (GNG) instead of TCA
• 3. Since OAA is used by liver for GNG, acetyl CoA is channeled into ketogenesis. 

Rise is NADH shifts OAA to malate, pushing acetyl CoA away from GNG and into ketogenesis. 

• First 2 are same as FA oxidation
• 1. Magnitude of lipolysis (amount of FA released)
• 2. CPT1 and entry of acetyl CoA into mitochondria 
• 3. Entry of acetyl CoA into TCA cycle (lack of entry increases amount for ketone synthesis)
• 4. Increased glucagon increases syn of HMG CoA synthase
• 5. Lack of insulin. 

Liver lacks succinyl CoA acetoacetate CoA transferase (SCAACT) and can't activate acetoacetate to active CoA form.

So, acetoacetate and B-hydroxybutyrate are exported to peripheral tissue that DO have this enzyme. 

CoA comes from succinyl CoA

Then it must be converted to acetoacetate first.

Acetoacetate --> acetoacetate CoA --> acetyl CoA enters TCA cycle. 

RBCs bc no mitochondria

Hypoglycemia. Ketone bodies help save plasma glucose by offering themselves to peripheral tissues to create energy instead. 

No, it's a carboxylic acid. 

It has a compound that binds irreversibly to carnitine, CPT 1 and 2, as well as CoA reducing bioavailability for actaul energy production. W/o energy for GNG, glucose stores are depleted --> hypoglcyemia.