Fatty Acid Biosynthesis Cholesterol Metabolism- Lecture 68-69

Question 1

What is the net reaction of fatty acid biosynthesis?

Answer 1

8 acetyl CoA + 7 ATP + 14 NADPH –> C16 palmitoyl CoA + 7 CoA + 7 ADP + 7 Pi + 14 NADP

Question 2

When are fatty acids synthesized?

Answer 2

high levels of carbohydrates (glucose) and protein (amino acids)

Question 3

How are fatty acids synthesized in the liver exported for storage?

Answer 3

triglycerides packaged in very low density lipoprotiens (VLDL)

Question 4

What regulates fatty acid synthesis?

Answer 4

elevated by insulin

decreased by glucagon

Question 5

Why does high glucose result in fatty acid synthesis?

Answer 5

glucose –(pyruvate dehydrogenase)–> acetyl CoA (via glycolysis) which can enter TCA cycle and produce citrate
citrate can continue on to produce ATP (necessary for fatty acid synthesis) or leave mito (via tricarboxylic acid carrier) to re-form acetyl CoA which enters lipogenesis in the cytosol

Question 6

Describe the pathway of the citrate shuttle.

Answer 6

citrate leaves mito via tricarboxylic acid carrier
citrate –(citrate lyase)–> OAA + acetyl CoA
OAA –> malate
malate either re-enters the mito and is re-oxidized back to OAA and acetyl CoA (which can enter lipogenesis) OR
malate + NADP+ –(malic enzyme)–> Pyruvate + CO2 + NADPH

Question 7

What is the rate limiting step of fatty acid synthesis?

Answer 7

Acetyl CoA + ATP + CO2 –> malonyl CoA + ADP + Pi

via acetyl CoA carboxylase (ACC) + biotin cofactor

Question 8

What regulates acetyl CoA carboxylase?

Answer 8

activated by citrate and insulin (dephosphorylates ACC to activate/stimulates it)
inactivated by palmitoyl CoA (product), AMP-activated kinase (phosphorylates ACC to inhibit), glucagon/cAMP-PKA (phosphorylates ACC at different site to inhibit)

Question 9

What are the sources of NADPH for fatty acid synthesis?

Answer 9

first two steps of PPP pathway
malic enzyme under lipogenic conditions
transhyrogenase (see isocitrate shuttle)

Question 10

What are the two components of the fatty acyl synthase complex?

Answer 10

condensing enzyme (P-SH site)
acyl-carrier protein (SH-Cys site)

Question 11

Describe the formation of palmitoyl-CoASH via the FAS complex.

Answer 11

1. Acetyl CoA binds at the condensing enzyme and is transferred to the acel-carrier protein (SH-Cys site) when malonyl CoA binds the condensing enzyme (P-SH site)
2. condensation of malonyl CoA and Acetyl CoA produces Co2 + 4 carbon acetoacetyl group bound to the APC
3. reduction of 4 carbon acetoacetyl CoA (consumes one NADPH)
4. dehydration
5. second reduction (consumes one NADPH) produces a saturated 4-carbon butyryl CoA
6. repeat of the cycle with the 4-carbon butyryl CoA by attaching to the cystine SH of the condensing enzyme and condensing with malonyl CoA
   Final product: C16 palmitate (cannot bind to cys-SH domain)

Question 12

What is the net reaction of the FA synthase reaction?

Answer 12

8 acetyl CoA + 7 ATP + 14 NSDPH + 14H+ + 7H2O –> palmitoyl CoA + 7 CoA + 14 NADP+ + 7 ADP + 7 Pi

Question 13

What are the fates of palmitoyl CoA?

Answer 13

stored as triglycerides (esp in liver and adipose)
formation of phospholipids for membranes
elongation to produce C18, C20 fatty acids (not covered)
desaturated to produce unsaturated fatty acids (not covered)

Question 14

What regulates the FA synthase reaction?

Answer 14

acetyl CoA carboxylase (including metabolite and hormonal control)
adaptive control (lipogenic conditions activate genes for citrate cleavage enzymes, malic enzyme, acetyl CoA carboxylase, and FAS via transcription factor SREBP which is activated by insulin)
malonyl CoA (needed for fatty acid synthesis) is a powerful inhibitor of the acyl carnitine transferase (brings fatty acids into mito for beta-oxidation)

Question 15

What is included in the term eicosanoid?

Answer 15

prostaglandins, thromboxanes, leukotrienee

Question 16

What are eicosanoids?

Answer 16

potent regulators of cellular functions that are produced throughout the body
function as lipid hormones (local hormone effects)

Question 17

What are the prostaglandins involved in?

Answer 17

fever, inflammation, pain, blood dilation and flow (BP)

Question 18

What are the thromboxanes involved in?

Answer 18

regulating blood vessel tone, BP, platelet aggregation, clot formation

Question 19

What do both thromboxanes and prostaglandins contribute to?

Answer 19

inflammation by increasign capillary permeability, inducing local vasodilation (redness), promoting infiltration fo inflammatory cells, production of reactive O2 species, and pain

Question 20

What inhibits eicosanoids?

Answer 20

NSAIDS (eg. aspirin) and OTC analgesiscs

Question 21

What are the functions of cholesterol?

Answer 21

component of biological membranes; provide rigidity and order
precursor of bile salts; used to emulsify/digest fats (liver)
precursor of steroid hormones and vitamin D (endocrine)

Question 22

Describe the process of cholesterol synthesis.

Answer 22

Acetyl CoA (from glucose, fatty acids, or amino acids) –> –(HMG CoA synthase)–> HMG CoA (can branch here to become ketone bodies)
HMG CoA + 2 NADPH –(HMG-CoA reductase)–> mevalonate + 2NADP+
mevalonate + 3 ATP –> 3 ADP + isopentenyl pyrophosphate
isopentenyl pyrophosphate can become ubiquinone, polichol or can become cholesterol

Question 23

Describe the structure of cholesterol.

Answer 23

27 carbons based in sterol rings (making it not soluble)

Question 24

What is the rate limiting step of cholesterol synthesis?

Answer 24

HMG- CoA reductase

Question 25

What regulates the rate limiting step of cholesterol synthesis?

Answer 25

stimulated by active -OHG form of HMG CoA reductase (promoted by insulin which activates SREBP2 which activates HMG-CoA) and low cholesterol inhibited by inactive -OP form of HMG CoA reductase (promoted by glucagon/epi via PKA and AMP kinase) and cholesterol (inhibits SREBP2 processing and promotes HMG-CoA reductase ubiquitylation and proteasome degradation)

Question 26

How is liver HMG-CoA further metabolized?

Answer 26

lysed by HMG-CoA lyase into acetoacetate + acetyl CoA

Question 27

How is cytosolic HMG-CoA further metabolized?

Answer 27

reduced by HMG-CoA reductase to mevalonate --> cholesterol

Question 28

What are the major kinds of lipoproteins?

Answer 28

chylo-microns, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL), high density lipoproteins (HDL)

Question 29

What are chylo-microns?

Answer 29

made in the GI tract, they carry triglycerides (dietary derived)

Question 30

What are VLDLs?

Answer 30

made in the liver, they predominately carry fatty acids/triglycerides synthesized in the liver

Question 31

What are IDLs?

Answer 31

carry much of the cholesterol in our circulation

Question 32

What are LDLs?

Answer 32

packaged IDLs that store large amounts of cholesterol that can be taken up by cells after binding to LDL receptors (this releases the cholesterol into the cell after lysosomal degradation)

Question 33

What are HDLs?

Answer 33

made in liver and GI they have low cholesterol and triglyceride concentrations and are mostly proteins that bring the modest amounts of cholesterol back to liver and endocrine tissue from the peripheral tissues

Question 34

What are the possible types of damage to lipoproteins?

Answer 34

``` LDLR mutations (result in increased serum cholesterol and risk of heart attack/stroke/athlerosclerosis) oxidation of LDLs by ROS (leads to recognition by macrophages that swell when they endocytose them forming "foam cells" that clog endothelial space and result in plaques) ```

Question 35

How do you treat elevated blood cholesterol?

Answer 35

1. limit cholesterol in diet 2. treat with statins (inhibit HMG-CoA reductase and lower cholesterol synthesis) 3. if statins aren't tollerated (about 20% of pts) treat with cholestyramine resin (binds to bile acids preventing their reabsorption --> liver synthesizes more bile acids from the cholesterol, thereby lowering levels of cholesterol)