Lightbody's Review Flashcards
Describe the pathway that allows for Acetyl CoA to be removed from the mitochondria and used for fatty acid synthesis
- 2 things required for fatty acid synthesis: acetyl CoA and NADPH
- Citrate Shuttle: provides Acetyl CoA (moves from mitochondria to cytosol) and NADPH for fatty acid synthesis (NADPH is also provided by the pentose phosphate shunt) Note: Citrate is shuttled out of the mitochondria when energy levels are high and there is no need to go though the TCA cycle
Mitochondria:
- Pyruvate to Acetyl CoA + CO2 (pyruvate dehydrogenase complex)
- Pyruvate + bicarbonate to OAA (pyruvate carboxylase, requires ATP)
- OAA + Acetyl CoA to citrate + CoASH (citrate synthase)
- *** There is a transporter for citrate in the inner mitochondrial membrane, so the citrate can be transported via this tricarboxylate transport system to the cytosol (can also enter the TCA cycle)
Cytosol:
- Citrate to Acetyl CoA + OAA (ATP-citrate lyase, requires ATP)
- OAA to malate (MDH, NADH is oxidized)
- Malate to pyruvate + CO2 (malic enzyme, NADP+ reduced to NADPH)
- ***Pyruvate transported back into the mitochondria (can enter citrate shuttle or TCA cycle)
Describe Acetyl CoA carboxylase: mechanism, function and regulation
*** RATE LIMITING/ CONTROL STEP OF FA SYNTH
Function: MAIN: TO MAKE MALONYL-COA FROM ACETRYL COA TO START THE FA SYNTH (this is the first step of FA synth technically)
one enzyme, 3 activities:
- Biotin carrier protein
- biotin carboxylase
- transcarboxylase
Mechanism: Acetyl Coa –> Malonyl CoA using ATP and HCO3 (as carbon source)
enzyme contains a biotin cofactor
-CO2 (from HCO3) first carried by biotin and then CO2 is transferred to alpha carbon of acetyl CoA (using ATP) via the biotin arm to produce malonyl CoA;
Regulation: It is synthesized as inactive protomers,
- Allosteric regulation: Citrate activates it; Palmitoyl CoA (long chain FA) deactivates it
- Phosphorylation:
- Insulin activates protein phosphatase which dephosphorylates ACC and causes its activation
- Glucagon activates cAMP dependent kinase which phosphorylates it and causes deactivation
- Transcriptional regulation (SREBP’s): Insulin upregulates SREBP-1c which causes cleavage and increased transcription in the nucleus (for ACC)
Describe the Fatty acid synthase complex: physical makeup and mechanism
Structure: homodimeric multienzyme complex; each monomer (two total) is 270 kD long and has 7 enzymes activities; the 2 monomeers are linked in a head to tail fashion
Function: only synthesizes FA up to and including palmitic acid (C16); does not introduce double bonds
Mechanism: **only the very first step uses Acetyl CoA, rest use Malonyl CoA
- Acetyl CoA attaches to the ACP domain on FAS
- ACoA moves to a different cystein on FAS so that the ACP is now free
- Malonyl CoA (made in ACC) attaches to the ACP
- Acetyl group transferred onto Malonyl-ACP causes two things: a). CO2 comes off b). 2C’s added to alpha carbon of malonyl group (now a 4C IM on the ACP)
- Reduction reaction reduces carbonyl to a hydroxyl
- Dehydration produces a double bond
- Reduction reduces double bond leaving a 4C FA (saturate)
- Transfer of 4C onto cysteine residue to free up ACP so that it can happen again 9. Repeat; add 2C’s on until you get 16C
Describe how FA chain elongation occurs
FA’s are released from FAS as palimitate (16C, no saturation); in order to elongate past 16C need different enzymes;
Can elongate: FA’s produces by FAS, dietary saturated and unsaturated FA’s
Enzymes for elongation are located within the endoplasmic reticulum and mitochondria
FA’s are esterified to Coenzyme A (instead of ACP in FAS)
Malonyl CoA adds 2C per cycle similar to FAS except that in this situation a different enzyme does each step, instead of 1 enzyme
**Fatty Acid Elongase (EOVLC): catalyze the first condensation step by adding 2C’s onto the CARBOXY END
Describe how FA chain desaturation occurs
- Occurs on the ER -Uses 4 broad specificity fatty acyl-CoA desaturase enzymes
- Introduce double bounds at positions C4, C5, C6 or C9
- Humans cannot introduce double bounds beyond C9
- Double bonds are always in the cis position
Mechanism: Essentially taking O2 and reducing it to 2 waters (therefore need 4 electrons and 4H+)
Unsaturated fatty acid donates 2 electrons (2 H+)
The other 2 electrons (2H+) come from Ferrous State of cyt b5 (NADPH + H+)
How? NADPH–> NADP+ causes 2e- onto FAD+ –> FADH2 of cyt b5 reductase, then FADH2 –>FAD+ causes 2e- (one per heme) onto 2 Fe3+ –> 2 Fe2+ of two cyt b5
What is the significance of non-essential FA’s?
- Linoleic acid (18:2(9,12)) and linolenic acid (18:3(9,12,15)) are essential fatty acids that we cannot produce (double bonds beyond C9) and therefore must be obtained from the diet
- We can then use fatty acid elongases to elongate these dietary fatty acids (ie. to produce arachidonic acid, which is produced from chain elongation and desaturation of linoleic acid)
Describe the regulation of Lipogenesis
-Regulated by control of acetyl CoA carboxylase enzyme and a family of transcription factors known as sterol regulatory element binding proteins (SREBPs)
SREBPs:
- Directly activate genes associated with synthesis of cholesterol, fatty acids, TAGs and phospholipids
- Also activate genes associated with the synthesis of NADPH (required to make these molecules)
- Synthesized as inactive precursors bound to the ER
- released by a serine protease and translocated to nucleus where they activate transcription
SREBP-1c:
- activates transcription of genes required for the synthesis of fatty acids and phospholipids
- Insulin stimulates the action of the protease that cleaves SREBP-1c from the ER and enhances its translocation into the nucleus (increase transcription)
- Unsaturatated fatty acids inhibit the protease that cleaves SREBP-1c from the ER (decrease transcription)
- Enzymes stimulated by SREBP-1c:
- Acetyl CoA carboxylase
- Fatty acid synthase
- Fatty acid elongases
- Fatty acyl-CoA
- desaturases
- GPAT (glycerol 3P acyltransferase)- used to produce TAGs
Describe the characteristics of white adipose tissue
= A large lipid droplet occupying almost the entire cell
- Constitutes the major energy storage depot in humans
- When energy intake of the body exceeds energy utilization, excess energy is stored as TAG in white adipose tissue
- As TAG accumulates, a few things happen:
- Adipocytes increase in size until a maximum size reached, at which point they divide
- Preadipocytes differentiate into adipocytes (from a pool of proliferating preadipocytes in vasculature of adipocyte tissue)
- NOTE: currently thought that once adipocytes are present they are never lost, even if you lose weight (can only shrink/expand)
- White Adipose = largest endocrine organ in the body:
- Secretes many different factors that affect energy metabolism and can influence disease states (Ex) Leptin
Where is leptin produce? where are its receptors? what is its function
- Peptide with a tertiary structure similar to IL6 (cytokine) and is encoded by the obese gene (ob)
- Produced mainly by adipocytes and secreted into blood
- Leptin receptors found in Placenta, liver, muscle, lungs, so it’s thought to effect reproduction, angiogenesis, immunity, wound healing, bone remodeling, CV function
MAIN EFFECT: TO REGULATE APPETITE, ENERGY INTAKE AND EXPENDITURE
Obeses individuals have higher concentrations of leptin than non-obese individuals
Describe the effect of Lepitn/defective leptin
People with genetic defect in ob gene or leptin R gene are hyperphagic and always obese
-Giving these people leptin injections decreases food intake, increases metabolism, and causes weight loss
How is Leptin’s effect mediated?/// what’s its mechanism of action
Leptin mediates through the arcuate nucleus of the hypothalamus
- Orexigenic neurons: increase appetite and decrease metabolism(produce NPY and AgRP neuropeptides)
2, Anorexigenic/POMC neurons: inhibit appetite and increase metabolism
**Both produce an inhibitory effect on eachother
LEPTIN: Activates POMC (anorexigenic neurons) and inhibits NPY (orexigenic neurons)
So: if a there is a hunger signal = decrease in leptin which causes activation of NPY/AgRP and inhibition of POMC; thus appetite is increased and metabolism is decreased (opposite for satiety)
POMC and AgRP act on the alpha MSH Pathway: POMC causes + alpha-MSH = decreased appetite AgRP causes - alpha-MSH = increased appetite
Why does sleep deprivation result in obesity?
because lack of sleep result in lowering of brain leptin levels (so then causes your appetite to be larger and metabolism to be slower)
Describe the normal (general) response to insulin in the adipocytes/muscles; how does this differ from the liver?
Dietary glucose stimulates the pancrease to make insulin; insulin then acts on adipocyte and muscle to induce GLUT transporter to take up glucose; The liver also takes up glucose, but it does not need a signal from insulin to present its GLUT because the transporters are always present;
What is the effect of insulin on the liver?
Liver shuts down gluconeogenesis (glucose synthesis stopped in the liver); Increases SREBP-1c: so now the liver synthesizes more TAGs from excess glucose (which are then secreted from the liver and stored in the adipocytes)
What happens in type 2 diabetes with respect to function of the liver, skeletal muscle, and apidocytes and regulation of glucose pathways?
Type 2 diabetes = insulin resistance; therefore increased blood glucose stimulates the pancreas to make insulin but the body can’t respond to the insulin; This means that the GLUT expression is not stimulated, so the muscles and adipocytes do NOT take up glucose;
In the liver, gluconeogenesis is not shut down, so synthesis continues, leading to hyperglycemia
The even more increased glucose (hyperglycemia) causes even more insulin secretion from the pancreas, resulting in HYPERINSULEMIA;
BUT INSULIN STILL STIMULATES THE SREBP-1C so TAGs are still synthesized, and a lot of synthesis occurs because we have tons of insuling, this leads to hyperlipogensis which leads to hyperlipidemia; = EXCESS FAT IN THE LIVER AND MUSLCES
This excess FA synthesis and secretion of leads to excess FA in the serium, adipose, and muscle; this further prevents glucose uptake by muscle (because we have fat/energy, dont need glucose in there now)
Eventually the pancreas wears itlsef out and stops producing insulin; at this point there is a progression from insulin resistance to type 2 diabetes mellitus
