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Lipoprotein transport of fats + Biosynthesis membrane lipids & Steroids

Q: What are the functions of fatty acids?

1. Fatty acids are fuel molecules . They are stored as triacylglycerols (uncharged esters of fatty acids with glycerol). Mainly stored in adipose tissue. Fatty acids mobilized from triacylglycerols are oxidized to meet the energy needs. 2. Fatty acids are building blocks of phospholipids and glycolipids (biological membranes). 3. Many proteins are modified by the covalent attachment of fatty acids, which targets the proteins to membrane locations. 4. Fatty acid derivatives serve as hormones and intracellular messengers .

Q: What are the basic steps of fatty acid oxidation?

1. An activated fatty acid is oxidized to introduce a double bond 2. The double bond is hydrated to introduce a hydroxyl group 3. The alcohol is oxidized to a ketone 4. The fatty acid is cleaved by coenzyme A to yield acetyl CoA and a fatty acid chain 2 carbons shorter. Activated acyl group --> Oxidation (FAD > FADH2) --> Hydration --> Oxidation (NAD+ > H+ + NADH) --> Cleavage (coenzyme A) --> Activated acyl group + Activated acetyl group

Q: How is cholesterol produced?

2 Acetyl CoA's are formed together by thiolase to get Acetoacetyl CoA . Together with Acetyl CoA this forms HMG-CoA , catalyzed by HMG-CoA synthase . HMG-CoA reductase converts HMG-CoA into mevalonate , which goes into the mevalonate pathway to form isopentenylpyrophosphate . This is then converted into Squalence and then Lanosterol and ultimately Cholesterol.

Q: What does MHG-CoA reductase do?

HMG-CoA reducatse is the rate limiting enzyme of the cholesterol pathway, it form mevalonate from HMG-CoA .

Q: How are phospholipids and triglycerides synthesized?

- DHAP (dihydroxyacetone phosphate) is formed by the gluconeogenic pathway from glucose . DHAP is coverted into Glycerol 3-phosphate and this enters the endoplasmic reticulum where it is converted into Phosphatidate (which is the same as DAG-3P ). Phosphatidate reacts with alochol to form a phospholids. * For phospholipid synthesis, either phosphatidate or alcohol must be activated by reaction with a NTP. - Triacylglycerol is degraded into glycerol and free fatty acids . Glycerol is phosphorylated into Glycerol 3-phosphate . Which follows the same pathway to create Phospholipids. - Phosphatidate can be converted into triacylglycerol in the liver.

Q: What is the difference between phospholipids and triglycerides?

- Phospholipids: Polar group - glycerol - 2 fatty acid chains - Triglycerides: glycerol - 3 fatty acid chains (storage & oxidation)

63 important questions on Lipoprotein transport of fats + Biosynthesis membrane lipids & Steroids

What are the functions of fatty acids?

1. Fatty acids are fuel molecules. They are stored as triacylglycerols (uncharged esters of fatty acids with glycerol). Mainly stored in adipose tissue. Fatty acids mobilized from triacylglycerols are oxidized to meet the energy needs.

2. Fatty acids are building blocks of phospholipids and glycolipids (biological membranes).

3. Many proteins are modified by the covalent attachment of fatty acids, which targets the proteins to membrane locations.

4. Fatty acid derivatives serve as hormones and intracellular messengers.

What are the basic steps of fatty acid oxidation?

1. An activated fatty acid is oxidized to introduce a double bond
2. The double bond is hydrated to introduce a hydroxyl group
3. The alcohol is oxidized to a ketone
4. The fatty acid is cleaved by coenzyme A to yield acetyl CoA and a fatty acid chain 2 carbons shorter.

Activated acyl group --> Oxidation (FAD > FADH2) --> Hydration --> Oxidation (NAD+ > H+ + NADH) --> Cleavage (coenzyme A) --> Activated acyl group + Activated acetyl group

How is cholesterol produced?

2 Acetyl CoA's are formed together by thiolase to get Acetoacetyl CoA. Together with Acetyl CoA this forms HMG-CoA, catalyzed by HMG-CoA synthase. HMG-CoA reductase converts HMG-CoA into mevalonate, which goes into the mevalonate pathway to form isopentenylpyrophosphate. This is then converted into Squalence and then Lanosterol and ultimately Cholesterol.

What does MHG-CoA reductase do?

HMG-CoA reducatse is the rate limiting enzyme of the cholesterol pathway, it form mevalonate from HMG-CoA.

What are the basic steps of fatty acid synthesis?

Reverse of oxidation

1. Condensation
2. Reduction
3. Dehydration
4. Reduction

Activated acyl group + Activated malonyl group --> Condensation --> Reduction --> Dehydration --> Reduction --> Activated acyl group

Why are triacylglycerols so high in energy?

They are reduced (much more than carbohydrates or proteins) and anhydrous (contain no water).

* A gram of nearly anhydrous fat stores 6.75 times as much energy as a gram of hydrated glycogen

Which membrane lipids are there mainly?

- Phospholipids
- Sphingolipids
- Cholesterol

How are phospholipids and triglycerides synthesized?

-DHAP (dihydroxyacetone phosphate) is formed by the gluconeogenic pathway from glucose. DHAP is coverted into Glycerol 3-phosphate and this enters the endoplasmic reticulum where it is converted into Phosphatidate (which is the same as DAG-3P). Phosphatidate reacts with alochol to form a phospholids.
* For phospholipid synthesis, either phosphatidate or alcohol must be activated by reaction with a NTP.

- Triacylglycerol is degraded into glycerol and free fatty acids. Glycerol is phosphorylated into Glycerol 3-phosphate. Which follows the same pathway to create Phospholipids.

- Phosphatidate can be converted into triacylglycerol in the liver.

What is the difference between phospholipids and triglycerides?

- Phospholipids: Polar group - glycerol - 2 fatty acid chains
- Triglycerides: glycerol - 3 fatty acid chains (storage & oxidation)

For what is phosphatidyl inositol (PI) important?

PI is important for signal transduction (PIP, PIP2, PIP3)

What are the main functions of cholesterol?

- Membrane flexibility (makes membranes stiff)
- Bile production (is precursor of bile)
- Hormones (precursor of steroid hormones)

How do LXR and SREBP regulate cholesterol synthesis?

- Much cholesterol in cell --> Less uptake cholesterol, promote cholesterol efflux, inhibit cholesterol synthesis --> LXR (Liver X Receptor).
* Promotes o.a. ABCA1

- Little cholesterol in cell --> more cholesterol in cell, inhibit cholesterol efflux, promote cholesterol synthesis --> SREBP (Sterol Regulatory Element Binding protein)
* Promotes o.a. HMG-CoA reductase

How does SREBP alter the transcription of cholesterol genes?

- SREBP is bound in the ER to SCAP by Reg (Regulatory domain)
- Cholesterol level falls
- SCAP & SREBP go to Golgi complex
- SREBP is cleaved off by serine protease & metalloprotease
- SREBP travels to nucleus

* SREBP stays in its place because of its sterol binding domain; low sterol levels --> travels to Golgi

How are cholesterol and triacylglycerols transported in body fluids?

In the form of lipoprotein particles.

Why are lipoprotein particles important?

1. Lipoprotein particles are the means by which triacylglycerols are delivered to tissues, from the intestine or liver, for use as fuel or storage.
2. The fatty acid constituents of the triacylglycerol components of the lipoprotein particles are incorporated into phospholipids for membrane synthesis.
3. Cells are not able to degrade the steroid nucleus (cholesterol). The cholesterol must be used biochemically or excreted by the liver.

What are the roles of apoproteins (proteins on the lipoprotein)?

1. Solubilize hydrophobic lipids
2. Contain cell-targeting signals

By which organs are apoprotein (Apolipoproteins) secreted?

Liver & intestine

How are the triacylglycerols in chylomicrons released?

Through hydrolysis by lipoprotein lipases.

* The liver takes up the cholesterol-rich residues (chylomicron remnants).

What happens to the excess of Triacylglycerols and cholesterol of the liver's own needs?

The triacylglycerols and cholesterol are exported into the blood in the form of VLDL (Very Low Density Lipoproteins).
* VLDL is stabilized by apo B and apo E

What happens to triacylglycerols in VLDLs (as in chylomicrons) ?

They are hydrolized by lipases on capillary surfaces, with the released fatty acids being taken up by the muscle and other tissues. The resulting remnants, which are rich in cholesteryl esters, are calles intermediate-density lipoproteins (IDL).

What happens to Intermediate-density lipoproteins (IDL)?

They are created out of VLDL, where the fatty acids were taken up by muscle and other tissues.
They have 2 fates:
1. Half of them are taken up by the liver for processing
2. Half are converted into low-density lipoprotein (LDL) by the removal of more triacylglycerols by tissue lipases that absorb the released fatty acids.

What is the role of low-density lipoprotein (LDL)?

The role of LDL is to transport cholesterol to peripheral tissues and regulate de novo cholesterol synthesis at these cells.

What is the role of high-density lipoprtoein (HDL)?

HDL picks up cholesterol released into the plasma from dying cells and from membranes undergoing turnover and delivers the cholesterol to the liver for excretion.

* An acyltransferase in HDL esterifies these cholesterols, which are then returned by HDL to the liver.

What does Lipoprotein lipase (LPL) do to triglycerides and where is it located?

LPL hydrolyzes the triglycerides

Triglyceride + H₂O ----> Fatty acids + glycerol

- Localisation: outside of the cell membrane of endothelial cells that cover the capillaries.
(LPS is not produces by endothelial cells!!!)

How does the cholesterol get released from the LDL particles when inside a cell?

By endocytosis;
- Apoprotein B100 (on surface LDL particle) binds to LDL receptor (on plasma membrane nonhepatic cells).
- The complex invaginates to form an endosome (clathrin)
- Travels to lysosome where it leads to the degradation of LDL and the release of cholesterol

Where can unesterified cholesterol be used for? And reesterified?

- Unesterified: membrane biosynthesis
- Esterified: storage inside the cell

How is cholesterol reesterified?

Free cholesterol activates Acyl CoA: cholesterol acyltransferase (ACAT). This esterfies the free cholesterol which results in more storage and membrane protection (too much cholesterol makes membrane unstable).

How is reverse transported out of the cell controlled?

By ABCA-1 (ATP-binding casette transporter I), which is controlled by LXR.
APOA1 and LCAT (Lecithine cholesterol acyl transferase) are also involved.

* A defect in ABCA-1 leads to Tangiers disease

Where do lipoproteins cosist of?

- Phospholipids
- triglycerides
- cholesterol (-esters)
- Apolipoproteins

What does LCAT (Lecithine cholesterol acyl transferase) do?

It converts cholesterol into a cholesterol-ester.

Cholesterol + Lecithine (PC) --> Cholesterol-ester + Lysolecithine

So you get an increased LysoPC in the HDL membrane.

* This is in the reverse route

What does CETP (Cholesteryl ester transfer protein) do?

Transfers Cholesteryl from HDL to VLDL,IDL and LDL, so that ik can take up more CE from the periphery before it passes the liver.

IDL and LDL will mostly be taken up by liver and thus CE will arrive in liver for excretion also via this route, so HDL can take up more CE from the periphery before it passes the liver.

How does the absence of the LDL receptor lead to hypercholesterolemia?

In familial hypercholesterolemia the total concentration of cholesterol and LDL in the blood plasma is markedly elevated.
- Because the LDLR is impaired, the entry of LDL into the liver and other cells is also impaired, leading to an increased level of LDL in the blood plasma. Also, less IDL enters liver cells because IDL entry is also mediated by the LDL receptor. So, IDL stays in the blood longer and more of it is converted into LDL than in normal people.

How does familial hypercholesterolemia cause inflammation (atheroscrelosis)?

LDL accumulates under the endothelial cells lining the blood vessels. There is an oxidation of the excess LDL to form oxidized LDL (oxLDL), which can instigate the inflammatory response by the immune system.

- The oxLDL is taken up by the immune system cells calles macrophages, which become engorged to form foam cells. These foam cells become trapped in the walls of the blood vessels and contribute to the formation of atherosclerotic plaques that cause arterial narrowing and lead to heart attacks.

How does HDL protect against artherosclerosis?

- HDL's best-characterized property is the removal of cholesterol from cells, especially macrophages. HDL retrieves cholesterol from other tissues in the body to return the cholesterol to the liver for excretion as bile or in the feces (reverse cholsterol transport).
- Macrophages that collect cholesterol from LDL normally transport the cholesterol to HDL particles. The more HDL, the more readily this transport takes place and the less likely that the macrophages will develop into foam cells.

What is tangier disease?

In tangier disease there is a deficiency in one of the proteins involved in the reverse cholesterol transport. It leads to a HDL deficiency.
- ABCA1 mutations leads to a HDL deficiency which leads to the accumulation of cholesterol in macrophages and premature atherosclerosis.

* Under normal conditions, apoA-I binds to ABCA1 to facilitate LDL transport. Also, the interaction between apoA-I and ABCA1 initiates a signal transduction pathway in the endothelial cells that inhibits the inflammatory response.

What are the 3 steps of lipolysis?

1. Mobilisation: triglycerides in the fat cells are broken down into glycerol and fatty acids, which are transported to other tissues.
2. Activation and transport: in these tissues the fatty acids are activated and transported into the mitochondria for degradation.
3. Degradation: fatty acids are broken down in step-by-step fashion into acetyl CoA. The acetyl CoA is oxidized in the citric acid cycle to CO2 and H2O, generating high-energy electrons that can be used to power synthesis of ATP (via respiratory chain)

Why is carnitine required for fatty acid breakdown? During which step?

Activation by Acyl CoA synthetase takes place in the outer membrane of the mitochondria. Acyl CoA can’t be transported over the inner membrane because it is too big. The tiny fatty acids (<12) can go diffuse through the membrane.
Carnitine has both negative and positive charge à can go easier through the membrane.
You have to have pools of CoA in the matrix.

Which enzyme catalyzes the first step in the B-oxidation cycle?

Acyl CoA dehydrogenase (double bond between C2 and C3). You have 3 isozymes (LCAD,MCAD & SCAD). You remove a proton and an electron to get a double bound. Those are stored on FAD (FAD --> FADH2).
Next step is hydrolysis by water addition to get the OH group.
Oxidation – Hydration – Oxidation – Thiolysis

Once you start transporting the fatty acids into the matrix you are committed to break it down (committed step), so carnitine acyltransferase I is the committed step of beta oxidation. After this, when the oxidation starts, you get the beta oxidation cycle.

Why does degradation of fatty acids by peroxisomes first yield less energy?

FADH2 is needed to produce the O2 from the H2O2 produced by the peroxisome. You will therefore have less FADH2 for ATP production in the oxidative phosphorylation.FADH2 can’t go out of the peroxisomes (too big) and is liberated as heat, so you will lose the energy from that. Acetyl CoA and NADH still can go out.

How is acetyl CoA carboxylase (which forms malonyl-CoA) regulated?

At first, ATP is needed for the reaction, so you need to be in a ‘high energy’ state with enough ATP. Therefore, insulin activates the carboxylase. In contrast to glucagon and epinephrine which inhibit it. Furthermore, citrate activates acetyl-CoA carboxylase (as it indicates a high energy state) and palmitoyl CoA inhibits the formation of malonyl-CoA (product inhibition).

How does malonyl-CoA affect fatty acid oxidation?

Malonyl-CoA inhibits the enzyme carnitine acyltransferase I which converts carnitine into acyl carnitine at the cytosolic side. Therefore, the ‘fatty acids’ cannot go into the mitochondria anymore and acyl-CoA can’t reach the mitochondria, which is needed for fatty acid oxidation.The synthesis stops the breakdown.

How are triacylglycerols degraded?

By lipases: intestinal enzymes, secreted by the pancreas. They degrade triacyglycerols into free fatty acids and monoacylglycerol.

* The fatty particles are first coated with bile acids to make them more accessible.

How are dietary lipids trasnported?

Via chylomicrons. The triaceylglycerols are resynthesized from fatty acids and monoacylglycerols in the intestinal mucosal cells and then packaged into chylomicrons. The chylomicrons are released into the lymph system and the into the blood. These particles bind to membrane-bound lipases, primarly at adipose tissue and muscle, where the triacylglycerols are once again degraded into free fatty acids and monoacylglyderols for transport into the tissue.

* Chylomicrons also transport fat-soluble vitamins and cholesterol

What are the 3 stages of processing of lipid energy reserves stored in adipose tissue?

1. Mobilization: the lipids must be mobilized. Triacylglycerols are degraded to fatty acids and glycerol, which are released from the adipose tissue and transported to energy-requiring tissues.
2. Activation: At the tissues, the fatty acids must be activated and transported into mitochondria for degradation.
3. Degradation: The fatty acids are broken down in a step-by-step fashion into acetyl CoA, which is then processed into the citric acid cycle.

How do released fatty acids travel to the tissues?

The fatty acids bind to the blood protein albumin.

How can glycerol formed from lipolysis be used for bothe glycolysis and gluconeogenesis?

The glycerol formed by lyposis is absorbed by the liver and phosphorylated. It is oxidized to dihydroxyacetone phosphate, which is isomerized to glyceraldehyde 3-phosphate. This molecule is an intermediate in both glycolytic and gluconeogenic pathways.

What must first happen before the fatty acids can be oxidaized in the mitochondrial matrix?

The fatty acids are first activated through the formation of a thioester linkage to coenzyme A. This activation reaction takes place on the outer mitochondrial membrane, where it is catalyzed by acyl CoA synthethase.

The pyrophosphate is rapidly hydrolyzed by a pyrophosphatase.

1. Fatty acid + ATP <--> Acyl adenylate + PP_i2. Acyl adenylate + coenzyme A <--> Acyl CoA + AMP

How are double bonded en odd-numbered fatty acids degrades?

Additional enzymes isomerase and reductase.

Odd-numbered double bonds are handled by the isomerase, and even-numbered ones by the reductase and the isomerase.

What is the product of odd-numbered fatty acid degradation?

A propionyl CoA and an acetyl CoA (instead of 2 Acetyl CoA).

Propionyl CoA enters the citric acid cycle after it has been converted into succinyl CoA. This requires vitamin B₁₂.

What is the difference of fatty acid oxidation in peroxisomes and in the mitochondria?

Peroxisomes oxidize long chain (>20C) and branched fatty acids.

- In peroxisomes, acyl CoA dehydrogenase (flavoprotein) transfers electrons from substrate to FADH₂ and then to O₂ to yield H₂O₂.
- In mitochondrial B-oxidation, the high energy electrons would be captured as FADH₂ for use in the electron-transport chain.
- Because H₂O₂ is produced instead of FADH₂, peroxisomes contain high concentrations of catalase to degrade H₂O₂ into H₂O and O₂.

How can Acetyl CoA (from fatty acid oxidation) enter the citric acid cycle?

Acetyl CoA must combine with oxaloacetate to gain entry to the citric acid cycle.

* The availability of oxaloacetate depends on an adequate supply of carbohydrate.

What happens to Acetyl CoA (from fatty acid oxidation) when the supply of carbohydrates is insufficient?

Acetyl CoA needs oxaloacetate to enter the citric acid cycle.
-Oxaloacetate is normally formed from pyruvate, the product of glucose degradation in glycolysis, by pyruvate carboxylase.
- If there is no carbohydrates, the concentration of oxaloacetate is lowered and acetyl CoA cannot enter the citric acidic cycle anymore.
- In fasting or diabetes, oxaloacetate is consumed to form glucose by the gluconeogenic pathway (and unavailable for condensation with acetyl CoA).
- Acetyl CoA is diverted to the formation of acetoacetate and D-3-hydroxybutyrate (ketone bodies).

How are ketone bodies converted into acetyl CoA?

- Acetoacetate:
1. Acetoacetate is activated by the transfer of CoA from succinyl CoA (CoA transferase)
2. Acetoacetyl CoA is cleaved by thiolase to yield 2 Acetyl CoA
Acetyl CoA enters the citric acid cycle

- 3-Hydroxybutyrate:
First oxidized to produce acetoacetate (NAD+ --> NADH)

How is diabetic ketosis induced?

Insulin is absent:
- The liver cannot absorb glucose > cannot provide oxaloacetate > fatty acid-derived acetyl CoA cannot enter CAC > ketone bodies
- Adipose cells continue to release fatty acids into bloodstream > fatty acids taken up by liver > ketone bodies

Severe acidosis -> impairment in tissue function (most importantly CNS)

Why can't fatty acids be converted into glucose?

Acetyl CoA cannot be converted into pyruvate or oxaloacetate, so it cannot enter the gluconeogenic pathway.

* The reaction that generates acetyl CoA from pyruvate is irreversible.

What are the differences between fatty acid degradation and synthesis?

- Synthesis takes place in the cytoplasm, degradation primarily in the mitochondrial matrix.
- All the enzymes needed for synthesis are linked together as fatty acid synthase. Degradative enzymes are not linked covalently.
- The reductant in synthesis is NADPH, the oxidants in degradation is NAD+ and FAD.

How is fatty acid synthesis initiated?

Fatty acid synthesis starts with the carboxylation of acetyl CoA to malonyl CoA by acetyl CoA carboxylase. This irreversible reaction is the committed step in fatty acid synthesis.

How is acetyl CoA transported into the cytoplasm for fatty acid synthesis?

Acetyl CoA fuses together with Oxaloacetate into citrate. Citrate can be transported over the inner membrane into the cytoplasm. In the cytoplasm it is cleaved by ATP-citrate lyase, generating oxaloacetate. Oxaloacetate is converted into malate and this into pyruvate which goes back into the mitochondrial matrix to be converted into Oxaloacetate.

* The presence of citrate in the cytoplasm inhibits phosphofructokinase

How is the NADPH needed for ATP synthesis yielded?

1. 1 molecule of NADPH is generated for each molecule of acetyl CoA that is transferred from mitochondria to the cytoplasm.
(When oxaloacetate is converted into Malate)
2. The additional molecules of NADPH come from the pentose phosphate pathway.

Where and how does fatty acid elongation occur?

- On the cytoplasmic face of the endoplasmic reticulum membrane
- Malonyl CoA is the 2C donor in the elongation of fatty acyl CoAs.
- Condensation is driven by the decarboxylation of malonyl CoA

How is fatty acid production/synthesis regulated via Acetyl CoA carboxylase?

- Acetyl CoA carboxylase 1 is switched off by phosphorylation and activated by dephosphorylation.
- AMP-activated protein kinase (AMPK) phosphorylates the carboxylase; activated by AMP, inhibited by ATP
- Citrate also allosterically stimulates the carboxylase; the level of citrate is high when both acetyl CoA and ATP are abundant
- Palmitoyl CoA disassembles the carboxylase & inhibits the translocase that transports citrate from mitochondria to the cytoplasm & inhibits glucose 6-phosphate dehydrogenase (NADPH generation in PPP)
- Malonyl CoA inhibits carnitine acyltransferase I, preventing the entry of fatty acyl CoAs into the mitochondrial matrix.

How do glucagon and epinephrine inhibit fatty acid synthesis?

The catabolic hormones switch off fatty acid synthesis by keeping the carboxylase the inactive phosphorylated form.

How does insulin regulate fatty acid synthesis?

- Insulin stimulates fatty acid synthesis by activating acetyl CoA carboxylase.
- Insulin activates the carboxylase by enhancing the phosphorylation and inactivation of AMPK by protein kinase B.
- Insulin also promotes the activity of protein phosphatase that dephosphorylates and activates acetyl CoA carboxylase.

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