Block 1: Fatty Acid Synthesis and Degradation:

Question 1

Dislipidemia

1. Lipid accumulation.

Theories:

• 1. Proteoglycan Binding
• 2. Binding to Matrix
• 3. Aggregation:

2. Macrophage Foam Cell Formation
3. Plaque Rupture
4. Regression

Answer 1

1.Accumulation of lipid (mainly cholesterol) inside walls of arteries (vessels).

• 1. LDL has chared Lys and Arg which bind proteoglycans within the vessel wall. Specifically, Heparin Sulfate Proteoglycan.
• 2. Binding to Matrix: LDL and Lipoprotein A have affinity for cellular matrix
• 3. Aggregation: small LDL passs through endothelium binds with other LDL and becomes too large to leave vessel wall.

2. Macrophage enters vessel wall to clean up retained LDL, however, LDL has been oxidized, changing conf of LDL allowing macrophage to classify it as foreign. Scavenger receptors in macrophages are activated so macrophages consume them and become large foam cells.
3. Macrophages become too large and die, releasing cytokines and maybe CRP; inflammation occurs and vessel wall endothelium changes confirmation; plaque breaks; thrombosis occurs
4. Regression: HDL can take cholesterol out of macrophages if dietary cholesterol is decreased.

Question 2

Hypercholesterolemia

Answer 2

elevated cholesterol in blood: thick tendons

Question 3

Hypertriglyceridemia

Answer 3

• Eruptive xanthomas
• lipemia retinalis (cloudy/milky white veins and arteries)

Treatment:

• Treat underlying disease (ie: diabetes); lifestyle modifications (weight loss, smoking cessation, etc); pharmacologic therapy (ie: Niacin, “fibrates” both lower triglycerides and increase HDL)

Question 4

Statins inhibit: ____.

Lower blood cholesterol by:____

Answer 4

Statins inhibit HMG-CoA reductase. This inhibits cellular production of cholesterol, which increases the production of LDL receptors. The increased amount of LDL receptors takes up LDL from the blood so that it does not build up in vessel walls.

Question 5

Breakdown of Triglycerides 1

Answer 5

1. Lipases from mouth, stomach, pancreas remove FAs from positions 1 and 3
2. Intestine senses FAs, hormone CKK is released to gallbladder, which contracts and delivers bile to the intestine. Bile (amphipathic) emulsifies the fatty acids. Bile salts recycled via the liver
3. Bicarbonate from pancreas is delivered (b.c of hormone secretin) to neutralize stomach acid so that pancreatic lipases can anchor to bile-emulsified lipid and cleave FA. Cholesterol esterase cleaves CE to cholesterols. Phospholipase A2 removes last FAs on triglyceride. These make a “mixed micelle”
4. Micelle is taken up by eneterocytes which re-esterify FAs and Cholesterol to make chylomicrons out of CEs and TGs.
5. Chylomicrons have ApoB 48 and get ApoC2 (allowing it to deliver FA to periphery) and ApoE (allowing it to bring FA and cholesterol to the liver in the form of the chylomicron remnant) from HDL

Question 6

VLDL

Answer 6

• VLDL transports triglycerides to the periphery from the liver when the liver has an excess of TGs.
• It has Apo B 100 on surface.
• VLDL remnant is endocytosed back into liver, where it can make LDL using hepatic lipase, which keeps TGs and sends C.E.s out in LDL to the periphery

Question 7

LDL

Answer 7

• Made from VLDL: VLDL uses hepatic lipase to take TGs to liver and C.E.s stay in LDL.
• LDL takes cholesterol from the liver to the periphery. It can bind to any cell that needs cholesterol (any cell with an LDL receptor)
• has ApoB 100
• LDLs can be damaged/oxidized in the blood, so scavenger receptors on macrophages pick them up. When they pick up too many, macrophages become foam cells.

Question 8

HDL

Answer 8

• HDL has ApoA1
• made in intestine and liver
• docks on macrophages and cells w excess cholesterol.
• brings excess cholesterol from teh periphery to the liver.

Question 9

FA synthesis:

1. location:
2. steps
3. regulation

Answer 9

1. in the cytoplasm
2. Steps (using FA synthase):

• condensation: malonyl CoA and acetyl coA bind
• reduction: 2 H are added to turn B-carbon ketone into hydroxyl (OH) (uses NADPH + H)
• dehydration: loses H20 to make double bond between Ca and Cb
• reduction: Adds 2 H with NADPH and H

3. Regulation:

Insulin: meal –> high sugar–> activates (dephosphorylates) ACC (generates maolnyl-CoA by adding CO2 to acetylCoA)–> malonyl CoA inhibits carnitine acyltransferase I, preventing FA entry into mitochondrial matrix

glucagon/epinephrine: activates cAMP dependent PKA which phosphorylates and inactivates ACC. Concentration of malonyl CoA falls, FA enter mitochondrial matrix; glucagon also triggers mobilization of FA out of adipose tissues and into the blood

citrate= acetyl CoA precursor (substrate) activates ACC

palmitate (FA product) inactivates ACC

Question 10

FA degredation (Beta-ox)

1. Location
2. Steps
3. Regulation
4. Generates:
5. Utilizes:

Answer 10

1. In Mitochondria
2. Steps:

• Carnitine shuttle: takes FA from cytosol into mitochondria where beta ox takes place
• dehydration: remove 2 H using FAD
• hydration: add H20
• dehydration: lose 2 H using NAD
• Cleave: CoA grabs acetyl and leaves behind original FA minus 2 C

3. Malonyl CoA (synthesis precursor) inactivates carnitine shuttle
4. Generates: (Cn/2)-1 NADH and FADH but Cn/2 acetyl CoA
5. utilizes the equivalent of 2 ATP (ATP–> AMP) during carnitine transport and hence subtract 2 ATP from net gain of ATP

Question 11

Artherosclerosis and Hypotheses:

1. Oxidized LDL hypothesis
2. Inflammatory Model
3. Blood clot Model
4. Treatment

Answer 11

Foam cells undergo apoptosis when they are too large;

1. LDL can be oxidized and oxidized LDL is cleared by scavenger receptors
2. suggests that damage to the endothelial lining of vessels is the first problem (ie: hypertension, smoking, obesity, autoimmune disease, etc) followed by accumulation of LDL
3. blood clotting is part of vascular damage
4. diet, cholesterol lowering drugs, statins, HDL infusions

Question 12

Ketone Bodies:

Answer 12

• Excess Acetyl CoA from FA degradation makes ketone bodies in the liver to transport energy building blocks around the body. In starving state, glucose is absent and ketone bodies rise.
• Liver does not use KBs well, so they are transported to other organs for use.

Question 13

MCAD deficiency:

1. mechanism
2. symptoms
3. MOI
4. treatment

Answer 13

medium chain acyl-coA dehydrogenase deficiency

1. inability to break down medium chain FAs into acetyl CoA in mitochondria
2. vomiting, diarrhea, lethargy, FA changes in liver (med chains occur in liver), lots of medium length FAs on acylcarnitine profile (mass spec), non-ketotic hypoglycemia
3. AR
4. limit med chain FAs, long chain FAs may be okay if peroxisomes can degrade them

most common metabolic disorder. symptoms occur with metabolic stress (ie: fasting, EtOH, surgery, etc)

Question 14

LCAD deficiency:

1. mechanism
2. symptoms
3. MOI
4. treatment

Answer 14

1. defective LCAD enzyme (long chain fatty acids cannot be broken down in mitochondria. pregnant mothers with LCAD babies get fatty liver and cannot handle excess long chains
2. vomiting, diarrhea, lethargy, fatty changes in liver, lots of long chain FAs on acylcarnitine profile (Mass spec), non-ketotic hypoglycemia; muscle pain/damage (long chains used in muscle)
3. remove long chains from diet, avoid metabolic stresses; carnitine supplements can help

Long chains need carnitine to transport into mitochondria; med and small chains may not

Question 15

known predictors of coronary artery disease

Answer 15

• hypertension, smoking, HDL