Lipid Metabolism

Question 1

Overview of fatty acids

Answer 1

• Energy source for many cells
• Triacyglycerol are digested within the lumen of the S.I

Question 2

What is meant by exogenous & endogenous pathway?

Answer 2

• Exo: The absorption of TGs & other lipid nutrients and their distribution to the body’s tissues via lipoproteins
• Endo: where lipoproteins transport lipids that are produced in the liver to the body’s cells (starts in the liver with VLDL and ends with the release of cholesterol in the cells from LDL)

Question 3

What is the importance of the acetyl-CoA molecule in lipid metabolism?

Answer 3

• The energy rich molecule composed of coenzyme-A and two acetyl carbon group, it is the product of fatty acid degradation and the precursor for its synthesis

Question 4

How are lipids digested and transported in our body?

Answer 4

A) short & medium chain fatty acids are transferred to the blood stream where they bind to albumin in there

B) long-chain fatty acids, are delivered to enterocytes SER combining TGs with dietary cholesterol, new synthesized lipids & ApoB-48

1) Triglycerols (lipid class) is mixed with bile salts by pancreatic lipase producing monoacylglycerol + 2 fatty acids

2) monoaylglycerol and the two fat acids then are transported into the intestinal cells, where the 2 fatty acids joins with 2 CoA producing 2 Fatty acyl-CoA

3) 2 fatty acyl-CoA joins with monoacylglycerol producing triacylglycerol

4) triacylglycerol joins with proteins forming chylomicrons (ring of protein containing lots of TGs in its core)

5) chylomicrons are transported through the lymphatic capillaries (via exocytosis) to be stored in the adipocytes, where most of its contents are removed by the adipocytes tissues and skeletal muscles

Question 5

What is the importance of the triacylglycerol cycle?

Answer 5

• Regulates the level of fatty acids available to the body for energy generation and biosynthetic requirements
• Depending on the needs of the body it can be:

1) converted to TGs
2) degraded to generate energy
3) used for membrane synthesis

Question 6

What is meant by glyceroneogenesis?

Answer 6

It is the formation of glycerol-3-phosphate from substrates other than glucose or glycerol

Question 7

What are the steps in glyceroneogenesis?

Answer 7

In the adipocytes:

1) Malate (using NAD+) is converted into oxalacetate & NADH + H+

2) Oxaloacetate (utilizing GTP) using (PEPCK-C) is converted into Phosphoenolpyruvate and CO2

3) PEP is converted into dihydroxyacetonephosphate

4) DHAP (using NADH + H & glycerol-3-phosphate dehydrogenase) is converted into glycerol-3-phosphate and NAD+

Then glycerol-3-Phosphate is converted into triacylglycerol by its binding to 3 fatty acids

• The main enzymes for this pathway is pyruvate carboxylase (PC) & phosphoenolpyruvatecarboxykinase (PEPCK-C) which are mainly found in the adipose tissue and lactating mammary glands and in organs involved in gluconeogenesis (liver & kidney)

Question 8

What is meant by lipolysis?

Answer 8

As the energy reserves reduces, the body mobilizes its fats (TGs) into 3 fatty acids & glycerol, which occurs during fasting, vigorous exercises, and stress. Where then the fatty acids are transported into the target organelles via fatty acid binding proteins

Question 9

What is meant by the b-oxidation cycle?

Answer 9

Occurring in the matrix of the mitochondria it is:

• The breakdown of fatty acids into acetyl-CoA via removing two carbon fragments from the carboxylic end of fatty acids sequentially

Question 10

How is fatty acids transferred into the mitochondrial matrix?

Answer 10

1) fatty aids binds to coenzyme-A forming fattyacyl-CoA

2) Acyl-CoA + carnitine = acylcarnitine (via carnitine acyltransferase I) which can pass into the mitochondrial matrix via translocation carrier protein for b-oxidation to occur

3) carnitine acyltransferase II in the mitochondria will convert acylcarnitine not acyl-CoA & carnitine (which will exit the mitochondria again)

Question 11

What are the steps of the b-oxidation cycle?

Answer 11

It starts with Fatty acid binding with coenzymeA forming fatty acyl-CoA (utilizing 2 ATP):

1) fatty acyl-CoA is transferred into trans-a,b-enoyl-CoA via Acyl-CoA dehydrogenase utilizing FAD into FADH2 In a Oxidative reaction

2) trans-a,b-enoyl-CoA is converted into L-b-hydroxyacyl-CoA using enoyl-CoA hydrate utilizing H2O in a hydration reaction

3) L-B-Hydroxyacyl-CoA is converted into B-ketoacyl-CoA via l-b-hydroxyacyl-CoA dehydrogenase utilizing NAD+ into NADH + H+ In a oxidative reaction

4) b-ketoacyl-CoA is converted into acyl-CoA (reenters the cycle) + Acetyl-CoA (produces energy) via thiolase utilizing CoASH

Question 12

How many ATP molecules can be generated from the complete aerobic oxidation of a fatty acid?

Answer 12

Stearic acid = 122 ATP

Palmitic acid = 106 ATP

Question 13

What is meant by ketoacidosis?

Answer 13

High levels of ketone bodies in the blood

Question 14

What is meant by ketogenesis?

Answer 14

• The conversion of acetyl-CoA into ketone bodies (acetoacetate, b-hydroxybutyrate & acetone) When excess amounts of acetyl-CoA is produced
• Ketone bodies are used by cardiac and skeletal muscle as energy while the brain only uses it in prolonged starvation via converting b-hydroxybutyrate into acetoacetate then into 2 acetyl-CoA (Which can yield 20 ATP from the citric acid cycle giving a total of 21.5 ATP (when calculating the 2.5 atp from oxidation of b-hydroxybutyrate - 1ATP which is required to convert acetoacetate into acetoacetyl-CoA)

Question 15

When is acetone produced?

Answer 15

When acetoacetate levels are high during starvation and uncontrolled diabetes

Question 16

What is meant by fatty acid biosynthesis?

Answer 16

• Occurs in the cytoplasm mostly in the liver
• When the diet is low in fat and high in carbohydrate or protein (Mostly from excess carbohydrate)
• The large quantity of NADPH needed for this process is provided by the PentosePhospatePathway

Question 17

What are the steps in fatty acid biosynthesis?

Answer 17

When the mitochondrial citrate levels are high indicating high energy, citrate is transported into the cytoplasm is cleaved back into Acetyl-CoA and oxaloacetate (via citrate lyase), the acetyl-CoA cleaved is then used for fatty acid biosynthesis

First Acetyl-CoA is converted into Malonyl-CoA in a carboxylation reaction using ATP & CO2 producing ADP + Pi via the enzyme acetyl-CoA carboxylase (ACC) this reaction is irreversible using biotin as a cofactor

Then, Malonyl-CoA is converted into Malonyl-ACP utilizing ACP via the enzyme Malonyl-CoA-acetyl-CoA-ACP transacylase (MAT) then the fatty acid synthesis process starts

1) Adding acetyl-ACP to Malonyl-ACP will produce acetoacetyl-ACP producing CoASH & CO2 in a condensation reaction

2) acetoacetyl-ACP gets converted into b-hydroxybutyryl-ACP utilizing NADPH + H+ producing NADP+ in a redox reaction

3) b-3-hydroxybutyryl-ACP is then dehydrated into crotonyl-ACP removing a H2O molecule

4) cortonyl-ACP is then reduced into butyryl-ACP (4-C) utilizing NADPH + H+ producing NADP+

5) then the cycle keeps on repeating adding 2-carbons each time (repeated approx 7 times to produce palmitate) where at the end H2O is added to remove the ACP

Question 18

What is the differences between fatty acid biosynthesis and b-oxidation?

Answer 18

1) location: biosynthesis is in the cytoplasm while b-oxidation is in the mitochondria

2) enzymes

3) thioester linkages are found in the biosynthesis intermediates but not in the b-oxidation

4) electron carriers in biosynthesis reaction consumes NADPH and not NADH

Question 19

How is the enzyme ACC regulated?

Answer 19

Activated by:

1) Insulin (dephosphorylates the enzyme)
2) high Citrate (energy) levels

Inhibited by:

1) glucagon (phosphorylates the enzyme) activating AMP KINASE
2) Epinephrine
3) palmitoyl-CoA

Question 20

How is fatty acid biosynthesis regulated?

Answer 20

1) long-term regulation: alteration in the gene expression of the synthesis enzyme

2) short-term regulation: regulating the activities of the key regulatory enzymes by modifying the allosteric regulators covalently (phosphorylation/dephosphorylation) via hormones

Activated by:

1) Insulin (via activating ACC)
2) high citrate (activated ACC)

Inhibited by:

1) palmitoyl-CoA (depolymerization)
2) low energy

Question 21

What inhibits the b-oxidation?

Answer 21

Malonyl-CoA high levels

Question 22

How does AMP regulates Fatty acid metabolism?

Answer 22

AMP levels rises in response to stress, when AMP/ATP ratio rises (low energy) it activates AMPK switching from the anabolic “energy-consuming” pathway into the catabolic pathway “energy-generating” (b-oxidation) via phosphorylating ACC, it increases the fatty acid uptake into the cells and their transport into the mitochondria

Question 23

What does AMPK regulate?

Answer 23

Activates:

1) glucose uptake
2) glycolysis
3) fatty acid transport
4) fatty acid oxidation

Inhibits:

1) cholesterol synthesis
2) gluconeogenesis
3) glycogen synthesis
4) Lipolysis
5) lipogenesis
6) fatty acid synthesis

Question 24

How are the TGs removed from the chylomicron? And what happens to the chylomicron remnants afterwards?

Answer 24

• 90% of TGs are removed by the lipoprotein lipase the rest are hydrolyzed within the lysosomes releasing fatty acids & glycerol which can be metabolized by liver cells or stored
• Chylomicron remnants are removed by the liver, its cholesterol remnants can be 1. Esterified with fatty acids & packaged into lipoproteins, 2. Converted into bile acids

Question 25

What happens to the glycerol as the TGs are broken down?

Answer 25

It gets transported into the liver where it’s converted to VLDL

Question 26

What is meant by lipogenesis?

Answer 26

The synthesis of triacylglycerol (TGs) by the reaction of glycerol-3-phosphate or dihydroxyacetone with three acyl-CoA sequentially

Question 27

What is the structure of the fatty acid synthase (FAS) multi-enzyme complex?

Answer 27

X-shaped, head to head homodimer of two 272-kDa polypeptides, constructing two fatty acid simultaneously

Question 28

What are the steps in lipolysis?

Answer 28

In adipocytes:

1) binding of a hormone molecule such as one of the catecholamine or glucagon to specific adipocyte plasma membrane receptors

2) Hormone-receptor binding initiates a cAMP-mediated mechanism that activates protein kinase A (PKA)

3) Activated PKA phosphorylates perilipin-1, a protein on the surface of the cell’s lipid droplet that is associated with a protein called CGI-58

4) Once perilipin-1 is phosphorylated, its conformational change exposes TGs to 14 lipase-catalysed hydrolysis

5) The first and committed step in TG hydrolysis is catalysed by adipose triglyceride

6) The hydrolysis of diacylglycerol to yield monoacylglycerol and a fatty acid is catalysed by hormone-sensitive lipase (HSL)

7) Conversion of monoacylglycerol to glycerol and a fatty acid, catalysed by monoacylglycerol lipase (MGL)

-The products of lipolysis (fatty acids and glycerol) are released into the blood to bound to serum albumin. The albumin-bound fatty acids are carried to tissues throughout the body, where they are released from albumin and taken up by cells across the plasma membrane

Question 29

What additional enzyme is required by the oxidation of unsaturated fatty acid?

Answer 29

Oleic acid

Question 30

What is special about the oxidation of odd-chain fatty acids?

Answer 30

The last b-oxidation cycle of these molecules yields one acetyl- CoA and one propionyl-CoA, Propionyl-CoA is then converted to succinyl-CoA, a citric acid cycle intermediate

Question 31

How is fatty acid elongated and desaturated?

Answer 31

These processes are especially important in regulating membrane fluidity (done in the ER), The system efficiently introduces double bonds (desaturation) into long-chain fatty acids, Mediated by an electron transport system