PHRD-511: Lipid Metabolism

The presence of free fatty acids in the duodenum causes release of the peptide hormone _____.

cholecystokinin

produced in the small intestine

What does cholecystokinin do?

-causes gallbladder to release bile salts

-causes pancreas to release pancreatic lipase

What aids in the digestion of fats, cholesterol, and fat-soluble vitamins?

Bile salts

They do this by forming mixed micelles

What do mixed micelles do?

solubilize fats and render them accessible to digestive enzymes

Triglycerides must be _____ before absorption.

digested

What is the portal vein?

the main vessel of the portal venous system (PVS), which drains the blood from the gastrointestinal tract, gallbladder, pancreas, and spleen to the liver

Short-chain fatty acids (< C12) enter the portal vein and are transported directly to the _____.

Liver

What happens to the fatty acids that are too large to enter the portal vein?

They are absorbed by the intestinal mucosa and are re-esterified into triglycerides.

These triglycerides are incorporated into lipoprotein particles called chylomicrons, which enter the lymphatic vessels.

Triglycerides make up about _____ of dietary lipids.

90%

What do triglycerides consist of?

Three fatty acid chains linked by a glycerol backbone

What does pancreatic lipase do?

hydrolyzes triglycerides to give free fatty acids and 2-monoglycerides

These will be absorbed by intestinal mucosa cells

What enzymes lyse the ester bonds of triglycerides?

-Lingual Lipase (found in mouth)

-Pancreatic Lipase (found in intestines)

What are some sources of lipids?

-fats obtained from diet

-fats obtained from adipocytes

-fats synthesized in one organ for transport to another

What organ synthesizes most of the fats and sends them out to other cells?

The Liver

What are the steps for dietary and storage lipid processing in vertebrates?

Step 1: Biles salts emulsify dietary fats in the small intestine, forming mixed micelles

Step 2: intestinal lipases degrade triglycerides

Step 3: Fatty acids and other breakdown products are taken up by the intestinal mucosa and converted into triglycerides

Step 4: Triglycerides are incorporated with cholesterol and apolipoproteins into chylomicrons

Step 5: Chylomicrons move through the lymphatic system and bloodstream to tissue

Step 6: Lipoprotein lipase, activated by apoC-II in the capillary, converts triglycerides to fatty acids and glycerol

Step 7: Fatty acids enter myocyte (muscle) or adipocyte (fat) cells

Step 8: Fatty acids are oxidized as fuel or reesterified for storage

What are the two outcomes for fatty acids after processing?

-Oxidized for fuel

-Reesterified for storage as triglycerides

What are lipoproteins?

Soluble proteins that combine with and transport fat or other lipids in the blood plasma.

What lipoprotein comes from the extrinsic (exogenous) pathway?

Chylomicrons

Chylomicron composition is high in _____.

Triglycerides (84-89%)

What lipoproteins come from the intrinsic (endogenous) pathway?

-VLDL
-IDL
-LDL
-HDL

VLDL, IDL, LDL, and HDL are high in _____ and _____.

triglycerides; cholesterol

These lipoproteins are the main way that dietary cholesterol and cholesterol made by the liver get to other cells

What is the main protein component of chylomicrons and where is it made?

ApoB-48; intestine

What is the main protein component of VLDL and where is it made?

ApoB-100; liver

HDLs are involved in cholesterol transport from the _____ to the _____.

tissues; liver

VLDLs, IDLs, and LDLs are in cholesterol transport from the _____ to _____.

liver; tissues

After VLDL is sent out of the liver into the circulatory system, lipases start cleaving it until it eventually becomes _____. After more cleaving, that eventually becomes _____.

IDLs; LDLs

LDLs are sucked back up by hepatocytes (liver cells) and repackaged into VLDL before being sent back out into the circulatory system.

Through what process is LDL taken back up by the liver?

Receptor-Mediated Endocytosis

What happens if LDL is not taken back up by the liver and is instead left in the circulatory system?

atherosclerosis (hardening of arteries)

Where does fatty acid synthesis take place in the cell?

The cytosol

Where does the NADPH used during fatty acid synthesis come from?

The Pentose Phosphate Pathway

This comes from the oxidative phase

Where do the early stages of sterol synthesis occur in the cell? Where do the later stages occur in the cell?

Cytoplasm; Endoplasmic Reticulum

Where do phospholipid synthesis, fatty acid desaturation, and fatty acid elongation (>16 carbons) occur in the cell?

Endoplasmic Reticulum

Where does fatty acid oxidation occur?

Mitochondria

Where does fatty acid oxidation of fatty acids (>22 carbons) and bile acid conjugation occur?

Peroxisome

The process of storing fatty acids in adipose tissue is _____ mediated.

hormone

(the hormones are insulin, glucagon, and epinephrine)

How does insulin impact adipocytes and how does it do it?

It makes adipocytes store fats by blocking the phosphorylation of hormone sensitive lipase

What type of receptor does insulin signal through on adipocytes?

Tyrosine Kinase Receptor

What type of receptor does glucagon signal through on adipocytes?

G-Protein Receptor

How does glucagon impact adipocytes and how does it do it?

It makes adipocytes release fats by phosphorylating hormone sensitive lipase

What does hormone-sensitive lipase do?

It catalyzes the hydrolysis of stored fats in adipocytes so they can be released as fatty acids into the blood circulation as an energy source

Where does glycerol from triglycerides go after its catabolism?

Liver cells

Here, they undergo either glycolysis (to form pyruvate) or gluconeogenesis (to form glucose)

Where do fatty acids from triglyceride go after its catabolism?

Tissues

Here, they undergo fatty acid oxidation, TCA cycle, electron transport chain, and oxidative phosphorylation (to form energy for the tissue)

If glycerol is going back to the liver and fatty acids are being released for tissues, what hormone is high?

Glucagon

What is beta-oxidation?

The process of successive removal of 2-carbon fragments from fatty acids

Where does beta-oxidation occur?

-Mitochondria
-Peroxisome

What is omega-oxidation?

The process of successive removal of 2-carbon fragments from fatty acids

(This is the same as beta-oxidation, just from the other end)

Where does omega-oxidation occur?

-Endoplasmic reticulum of the liver and kidney of some vertebrate species

Fatty acids must be _____ before oxidation can occur.

activated

They are activated by CoA in the cytosol

_____ fatty acids diffuse freely across mitochondrial membranes.

Small (<12 Carbons)

How are larger fatty acids transported into the mitochondria?

Through the acylcarnitine/carnitine transporter (carnitine acyltransferase)

What is the rate limiting step for fatty acid oxidation?

The transport of fatty acids into the mitochondria

What molecule inhibits carnitine acyltransferase?

Malonyl-CoA

Where does the malonyl-CoA that inhibits carnitine acyltransferase come from?

Comes from the first committed step for fatty acid synthesis in the cytosol (acetyl-CoA carboxylase step) and pyrimidine catabolism

What does beta-oxidation of a fatty acid yield?

Acetyl CoA

This will be input into TCA cycle

If a 16-carbon chain undergoes beta-oxidation, how many acetyl CoAs would be produced? What if the chain was 24 carbons long?

8; 12

This is because the fatty acid is broken into 2 carbon segments

What is the final product of fatty acid oxidation?

ATP

Can unsaturated fats be catabolized the same way saturated fats are?

No

The double bonds need to be removed from the unsaturated fats first to make them saturated

What happens if you have an odd chain fatty acid that undergoes beta-oxidation?

A 3-carbon fragment will be left (propionyl-CoA)

To remove this, propionyl-CoA is converted to succinyl-CoA, a citric acid cycle intermediate

Where does beta-oxidation of long fatty acid chains (>22 carbons) and branched fatty acids occur?

The peroxisome

What are some differences of beta-oxidation in the mitochondria and peroxisome?

Reduction of FAD to FADH2

-Mitochondria: energy used to make ATP

-Peroxisome: energy lost as heat

Specificity of Fatty Acyl-CoAs

-Mitochondria: unbranched, <22 carbons

-Peroxisomes: branched, >22 carbons

What can glucogenic amino acids be broken down into?

Glucose Precursors

-pyruvate

-alpha-ketoglutarate

-succinyl-CoA

-fumarate

-oxaloacetate

What can ketogenic amino acids be broken down into?

-Fatty Acids

-Ketone Body Precursors (acetyl-CoA or acetoacetate)

Where does fatty acid biosynthesis mainly occur?

-Liver
-Adipocytes

Fatty acid synthesis and degradation (beta-oxidation) occur by _____ pathways.

different

When glucose is _____, large amounts of acetyl CoA are produced by glycolysis and can be used for fatty acid synthesis.

high

What are some differences between fatty acid beta-oxidation and fatty acid biosynthesis?

-Occur in different locations
-Use different acyl carrier groups
-One uses electron acceptor and other uses electron donor
-Different forms of C2 units produced/donated

What are the three main ways cells produce acetyl-CoA?

1. Amino acid degradation

2. Fatty acid oxidation

3. Glycolysis generates pyruvate, goes to mitochondria, converted to oxaloacetate and then into citrate which is transported in the cytosol. Here, ATP-citrate lyase converts citrate in cytosol to acetyl-CoA

What two molecules make citrate in the mitochondria during TCA cycle?

-Oxaloacetate
-Acetyl-CoA

How does citrate get out of the mitochondria and into the cytosol?

Through the tricarboxylate transport system

How many reactions are involved in fatty acid biosynthesis and where do these reactions occur?

7; in the cytosol

What is the main product of fatty acid biosynthesis?

Palmitic acid

Fatty acid biosynthesis reactions are _____ and _____.

endergonic; reductive

What is used for energy during fatty acid biosynthesis?

ATP

Where does the reductive power during fatty acid biosynthesis come from?

NADPH

A lot of this comes from the oxidative phase of the pentose phosphate pathway

What is the first committed step in fatty acid biosynthesis?

The carboxylation of acetyl-CoA by acetyl-CoA carboxylase (ACC)

This step is irreversible

Where does the acetyl-CoA that is carboxylated by acetyl-CoA carboxylase come from?

Citrate

The citrate comes from the TCA cycle in the mitochondria

What is the resulting product of the acetyl-CoA carboxylase step of fatty acid biosynthesis?

Malonyl-CoA

This will inhibit the carnitine acyltransferase used during beta-oxidation

What does malonyl-CoA inhibit in relation to beta-oxidation?

Carnitine Acyltransferase

This transfers fatty acids into the mitochondria for beta-oxidation, so if it is inhibited, fatty acids won't be transferred into the mitochondria.

How is the acetyl CoA carboxylase step of fatty acid biosynthesis regulated?

Through allosteric and hormonal control

What are the positive and negative regulators of acetyl CoA carboxylase?

Positive

-Insulin (hormonal regulation)

-High levels of citrate (allosteric regulation)

-High ATP levels (allosteric regulation)

Negative

-Glucagon and epinephrine (hormonal regulation)

-High levels of Palmitoyl CoA *this is the activated form of palmitic acid* (allosteric regulation)

-High AMP levels (allosteric regulation)

Will insulin activate or inactivate the acetyl CoA carboxylase step of fatty acid biosynthesis?

Activate

Will glucagon activate or inactivate the acetyl CoA carboxylase step of fatty acid biosynthesis?

Inactivate

What is a carbohydrate response element binding protein (ChREBP)?

Carbohydrate-signaling transcription factor

It is a nuclear receptor

What does a carbohydrate response element binding protein (ChREBP) do?

It senses the nutritional state of the body and upregulates the transcription and translation of the genes necessary for fatty acid synthesis.

What are the essential fatty acids (omega-3 fatty acids)?

-Linoleic acid
-Alpha-linoleic acid

These are precursors for arachidonic acid

What is the precursor for eicosanoids?

Arachidonic Acid

What are eicosanoids?

Potent short range signaling molecules (paracrine signaling)

Overall, what impact does high levels of insulin during the fed state have on lipid metabolism as a whole?

-Inhibits hydrolysis of stored triglycerides

-Stimulates formation of malonyl CoA, which inhibits carnitine acyltransferase

-Fatty acids remain in cytosol (fatty acid oxidation enzymes are in the mitochondria)

Overall, what impact do high levels of glucagon and epinephrine during the fasted state have on lipid metabolism as a whole?

-Epinephrine activates lipase enzyme to produce more fatty acids

-Glucagon inactivates malonyl CoA synthesis enzyme (leads to increased transport of fatty acids into mitochondria and the beta-oxidation pathway due to malonyl CoA no longer inhibiting carnitine acyltransferase)

Do the three fatty acids that are esterified to a triglyceride have to be the same?

No

They can be any fatty acid (even arachidonic acid)

True or False: Fatty acids can act as second messengers.

True

_____ is a key secondary lipid messenger for transducing signals downstream of many receptors.

Diacylglycerol (DAG)

Where does glycerol come from?

It comes from glycolysis

What do glucocorticoid hormones stimulate and suppress?

-Stimulate glyceroneogenesis and gluconeogenesis in liver

-Suppress glyceroneogenesis in adipose tissue

What does aspirin do in relation to prostaglandin synthesis?

Acetylates a specific serine residue of prostaglandin H2 synthase which blocks arachidonate from the active site

What do NSAIDS (i.e. acetaminophen, ibuprofen, meloxicam) do in relation to prostaglandin synthesis?

Bind noncovalently to the enzyme and also block the enzyme active site

What does thromboxane do?

Induces blood vesicle constriction and platelet aggregation

Regular low doses of aspirin reduce _____ production.

thromboxane

reduced thromboxane production reduces heart attack and stroke risk

What is cholesterol made from?

Acetyl-CoA

Where does the acetyl-CoA used during cholesterol biosynthesis come from?

Citrate