3001 - Lipid Intro and Lipoproteins

What is a triacylglycerol composed of?

One glycerol molecule esterified to three fatty acids.

What type of bonds connect fatty acids to glycerol in a triacylglycerol?

Ester bonds.

Must all three fatty acids in a TAG be identical?

No. They can include different saturated, monounsaturated, or polyunsaturated fatty acids.

What are major functions of triacylglycerols?

Energy provision, oxidation for energy, and energy storage.

What is a typical phospholipid composed of?

Glycerol, 2 fatty acids, phosphate, and a polar head group.

Why are phospholipids amphipathic?

They contain hydrophobic fatty-acid tails and a hydrophilic polar head.

Why does phospholipid amphipathicity matter?

It allows phospholipids to form biological membranes and interact with both aqueous and lipid environments.

What are several functions associated with phospholipids?

Membrane formation, signaling, and participation in receptor/ligand systems.

What are examples of phospholipid polar head groups shown in the lecture?

Choline, ethanolamine, serine, and inositol-containing groups.

What is structurally unusual about cardiolipin?

It contains three glycerol molecules, with a central glycerol linking two phosphatidic-acid moieties back-to-back.

How many fatty-acid chains are present in cardiolipin?

Four.

What molecule forms the backbone of phosphatidylinositol?

A glycerol-based phospholipid linked through phosphate to an inositol ring.

How can different phosphatidylinositol (Phosphoinositide) derivatives be generated?

By phosphorylating different positions on the inositol ring.

What is the structural backbone of sphingolipids? Describe its structure

Sphingosine.

Describe the R1 and R2 of the four types of sphingolipids

What structural feature characterizes sterols?

A fused four-ring steroid nucleus.

What major sterol is shown in the lecture?

Cholesterol.

What is a cholesteryl ester?

Cholesterol whose hydroxyl group has been esterified to a fatty acid.

What defines a saturated, monounsaturated, polyunsaturated (PUFA) fatty acid?

Saturated: It contains no carbon-carbon double bonds.

Monosaturated: It contains one carbon-carbon double bond.

Polyunsaturated: It contains two or more carbon-carbon double bonds.

What two PUFA families are specifically mentioned in the lecture?

n-3 and n-6 PUFAs.

Which enzymes begin TAG digestion before the small intestine?

Lingual lipase and gastric lipase.

Where is lingual lipase secreted, what substrate does it digest, and its primary site of action?

Secreted in the mouth.

It digests Triacylglycerol.

Its primary site of action is the mouth and stomach

Where is gastric lipase secreted, what substrate does it digest, and its primary site of action?

Secreted in the mouth.

It digests Triacylglycerols, particularly those containing medium-chain fatty acids..

Its primary site of action is the stomach

What is emulsification?

The physical dispersion of large fat droplets into smaller droplets.

Why does emulsification improve lipid digestion?

It increases the lipid-water surface area available to digestive enzymes.

What effect does lipid in the stomach have on gastric emptying?

It delays gastric emptying. It contributes to the relatively high satiety value of dietary fat.

In what conditions can lingual and gastric lipases make a particularly important contribution?

Pancreatic insufficiency, including cystic fibrosis and alcoholic pancreatic insufficiency.

What happens to triacylglycerols in the mouth?

Lingual lipase begins a small amount of digestion, breaking some triacylglycerols into diacylglycerol (DAG) and free fatty acids.

What happens to triacylglycerols in the stomach?

Gastric lipase continues digestion, especially removing short- and medium-chain fatty acids by hydrolyzing them from the sn-3 position, producing more diacylglycerol (DAG) and free fatty acids

What happens when lipids enter the small intestine?

Triacylglycerols, diacylglycerols, cholesterol, cholesterol esters, and phospholipids enter the small intestine, where most lipid digestion occurs.

What is the role of bile in triacylglycerol digestion (which occurs in the small intestine)?

Bile emulsifies fat into smaller droplets. It does not digest fat directly, but it increases the surface area available for digestive enzymes.

What is the main enzyme that digests triacylglycerols in the small intestine? What exactly does it do to digest TAG

• Pancreatic lipase, which is produced by the pancreas.

• It removes two fatty acids from triacylglycerol, producing monoacylglycerol (MAG) and two free fatty acids.

• Monoacylglycerol and free fatty acids are the final products of TAG digestion

  
  

What do micelles do during lipid absorption?

They transport lipid digestion products through the intestinal lumen toward the brush-border membrane.

• Lipid contents leave the micelle and move into enterocytes.

How are the products of lipid digestion absorbed after being transported by micelles? Do short- and medium-chain fatty acids get incorporated micelles for absorption?

• They can move across the brush border membrane into enterocytes. Transport proteins and diffusion can both be involved.

• No. According to the figure, short- and medium-chain free fatty acids can be absorbed without first being incorporated into micelles. They are small enough to just diffuse across the membrane

What happens to lipids after they enter the enterocyte?

They are reassembled. Monoacylglycerol and diacylglycerol are converted back into triacylglycerol, lysophospholipids are re-esterified into phospholipids, and cholesterol is esterified.

What happens to the re-formed triacylglycerols inside the enterocyte?

They are packaged with other lipids and apo-B48 to form chylomicrons.

How do chylomicrons leave the intestine?

They leave the enterocyte by exocytosis, enter the lymphatic system, and later enter the blood circulation.

What are the three portions of the small intestine? Into which region of the intestine are bile and pancreatic secretions delivered?

Duodenum, jejunum, and ileum.

• The duodenum is where bile and pancreatic secretions are delivered

How do bile and pancreatic secretions enter the duodenum, and what regulates their flow?

The gallbladder releases bile through the common bile duct, while the pancreas releases its secretions through the pancreatic duct, which joins the common bile duct.

• The sphincter of Oddi regulates the flow of these secretions into the duodenum.

What intestinal structures increase absorptive surface area?

Folds: In the small intestine, the mucosa and submucosa are arranged in folds

Villi: folds are covered with tiny, finger-like projections that line the inside of your small intestine to help your body absorb nutrients from the food you eat

Enterocytes: An absorptive epithelial cell lining the small intestine. Each villus contains one.

Microvilli: enterocytes are covered with microvilli, which make up the brush boarder.

What is the exocrine role of pancreatic acinar cells and duct cells?

Acinar: Secretion of digestive enzymes.

Duct: Secretes An aqueous sodium bicarbonate, NaHCO₃, solution, which helps neutralize acidic material entering the duodenum from the stomach.

What is an important endocrine function of the pancreas

Production of hormones such as insulin and glucagon.

Where are pancreatic lipase and colipase secreted, what do they digest, and where do they primarily act?

Secreted in he pancreas.

It digests Triacylglycerols

Its primary site of action is the small intestine

Fat digestion enzymes: Where is phospholipase secreted, what does it digest, and where does it primarily act?

Secreted in the pancreas.

It digests Lecithin and other phospholipids

Its primary site of action is the small intestine

Fat digestion enzymes: Where is Cholesterol esterase secreted, what does it digest, and where does it primarily act?

Secreted in he pancreas.

It digests cholesterol esters

Its primary site of action is the small intestine

Fat digestion enzymes: Where is Retinyl ester hydrolase secreted, what does it digest, and where does it primarily act?

Secreted in he pancreas.

It digests retinyl esters

Its primary site of action is the small intestine

Fat digestion enzymes: Where is Monoglyceride lipase secreted, what does it digest, and where does it primarily act?

Secreted in he small intestine.

It digests monoglycerides

Its primary site of action is the small intestine

What happens to MAG and fatty acids after entering the enterocyte?

They are re-esterified to rebuild TAG.

How is MAG → DAG → TAG in the enterocyte? Which enzymes are involved? What happens to TAG at the end?

1. MGAT, monoacylglycerol acyltransferase helps MAG to DAG

2. DGAT, diacylglycerol acyltransferase helps DAG to TAG

3. TAG is then packaged into chylomicrons in the enterocyte, which are delivered into the lymph, and move to peripheral tissues (circulation)

What are the three major stages of lipid absorption described in the lecture?

Uptake across the brush border, reassembly by esterification, and release into the circulation.

What is the key difference between a micelle and a chylomicron?

A micelle delivers digested lipid through the intestinal lumen, whereas a chylomicron transports reassembled lipid from the enterocyte through lymph and blood.

In what form is colipase secreted, What secretes this inactive form, and what activates it to colipase??

it is secreted by the pancreas as inactive procolipase, and is activated by trypsin

What is the main purpose of colipase?

Anchors the Enzyme: Colipase acts as a bridge. It binds to both the bile salts and the pancreatic lipase, anchoring the enzyme firmly to the surface of the fat droplet (the lipid-water interface) so it can break down fats before entering the enterocytes.

Stabilizes Structure: By attaching to the non-catalytic domain of lipase, colipase helps maintain the enzyme in an active, stable shape.

Why is colipase important in the presence of bile salts?

Bile salts can interfere with lipase attachment to fat droplets, and colipase prevents lipase displacement.

Which enzyme initially hydrolyzes dietary phospholipids? Which fatty acid position does phospholipase A₂ cleave? What are the products of phospholipase A₂ activity?

• Phospholipase A₂ (secreted by the pancreas)

• Cleaves the sn-2 fatty acid.

• Products are a lysophospholipid and 1 free fatty acid.

Where is lysophospholipase produced, and what does it further hydrolyze?

Enterocytes found at the brush-border membrane.

• It further hydrolyzes lysophospholipid at the sn-1 position to a glycerophosphoryl base and a free fatty acid.

What is the enzyme required and the products of cholesterol ester digestion?

Hydrolyzed to free cholesterol and free fatty acid by cholesterol esterase

What is passive diffusion across a membrane?

• Short-, medium-, and long-chain FA.

• Diffuse directly across the enterocyte membrane due to their lipophilic nature, moving down their concentration gradient from the lumen into the enterocyte.

What is active transport across a membrane?

• Fatty Acid Transport Proteins

  • Located in the enterocyte membrane, facilitate the uptake of long-chain fatty acids by actively transporting them into the enterocyte.

• CD36

  • Scavenger receptor

  • Plays a key role in the active uptake of long-chain fatty acids, facilitating their movement across the enterocyte membrane.

What is endogenous vs exogenous cholesterol?

Endogenous: Cholesterol delivered to the intestine through biliary secretions.

Exogenous: Cholesterol derived from the diet.

What happens to cholesterol that is not absorbed? What happens to much of the cholesterol that enters enterocytes?

Not absorbed: It is excreted.

Too much cholesterol: It is esterified before being transported in chylomicrons.

Which transporter moves cholesterol and phytosterols into the intestinal cell?

Niemann-Pick C1 Like 1 (NPC1L1)

What do ABCG5/G8 do?

Transport phytosterols and excess cholesterol from the enterocyte back into the intestinal lumen.

• Foods and supplements enriched with phytosterols effective at reducing blood cholesterol concentration by 10% or more

What is sitosterolemia?

A condition where the body absorbs and stores excessive plant sterols instead of removing them normally.

What is enterohepatic circulation?

Recycling of bile acids between the intestine and liver.

How are bile acids synthesized, recycled, and excreted in the body?

The liver synthesizes about 0.5 g of bile acids per day from cholesterol. The body maintains a bile acid pool of about 4.0 g, which is repeatedly recycled between the liver and intestine, with most bile acids reabsorbed in the ileum. About 0.5 g of bile acids are excreted per day in the feces.

Where is bile produced and stored?

Produced in the liver by cholesterol and stored in the gallbladder

What happens when the gallbladder contracts? What happens to bile acids after they help with lipid digestion?

Bile is released into the cystic duct, which joins the common bile duct, and then enters the duodenum.

• Most bile acids are reabsorbed in the ileum and returned to the liver through the hepatic portal vein.

What happens to dietary lipids in the intestinal lumen before absorption

They are emulsified (by bile) and digested by lipases, phospholipase, and colipase, producing molecules such as DAG, MAG, free fatty acids (FA), and lysophosphatidic acid (LPA) that can be incorporated into mixed micelles.

What does AGPAT (1-acylglycerol-3-phosphate O-acyltransferase) do inside the enterocyte?

AGPAT (1-acylglycerol-3-phosphate O-acyltransferase) converts lysophosphatidic acid (LPA) into phosphatidic acid (PA).

What does ACAT (Acyl-CoA:cholesterol acyltransferase) do during lipid absorption?

ACAT (acyl-CoA:cholesterol acyltransferase) converts free cholesterol into cholesteryl ester (CE)..

What is the role of MTP?

MTP (microsomal triglyceride transfer protein) helps assemble lipids with ApoB to form chylomicrons in the enterocyte.

• Chylomicrons then leave the enterocyte and enter the lymphatic system.

  • Like most lipoproteins, they allow hydrophobic dietary lipids to travel through aqueous lymph and blood.

What carries medium-chain fatty acids in portal blood that have passed from the enterocyte directly into the portal blood (no chylomicron formation)?

They bind to albumin and are transported directly to the liver

Why do lipids need to be packaged into lipoproteins for transport in the blood?

Lipids are hydrophobic, but blood is aqueous. Lipids such as phospholipids, triglycerides, cholesterol, and cholesteryl esters are therefore packaged with proteins into hydrophilic lipoprotein complexes.

Describe the basic structure of a lipoprotein particle.

A lipoprotein is a spherical particle with a surface made of apolipoproteins and a phospholipid monolayer, while the interior contains mainly triglycerides, cholesterol, and cholesteryl esters.

What are the four major classes of lipoproteins?

Chylomicrons, VLDL, LDL, and HDL.

What determines the density of a lipoprotein?

Density increases as protein and phospholipid content increase and decreases as triglyceride content increases.

Which lipoprotein has the highest vs lowest density and protein?

Highest: HDL

Lowest: Chylomicrons (because most TAG)

Which lipoprotein has the highest vs lowest free cholesterol?

Highest: LDL

Lowest: Chylomicrons (because most TAG)

Which lipoprotein has the highest vs lowest cholesterol esters?

Highest: LDL

Lowest: Chylomicrons

Which lipoprotein has the highest vs lowest cholesterol esters?

Highest: Chylomicrons

Lowest: HDL

What are the two major lipid transport systems?

Exogenous lipid transport system: Transports dietary triacylglycerols from the intestine to peripheral tissues for storage or energy use.

Endogenous lipid transport system: Transports fats and cholesterol made inside the body—primarily by the liver—out to peripheral tissues and cells

Describe the exogenous lipid transport pathway from chylomicron formation to liver uptake.

1. Dietary TAG is absorbed in the small intestine and packaged into chylomicrons containing ApoB-48 and ApoA-1, which enter the lymphatics and then the circulation.

2. Chylomicrons acquire ApoE and ApoC-II from HDL. They deliver TAG mainly to adipose tissue and muscle, where lipoprotein lipase (LPL) hydrolyzes TAG, releasing fatty acids and monoacylglycerols to tissues and glycerol into the blood.

   1. Because adipose tissue and muscle cannot phosphorylate glycerol, it is taken up by the liver or kidney. As much of the TAG is removed, the chylomicron becomes a chylomicron remnant.

3. The remnant returns ApoA and ApoC to HDL, then binds to the liver through a site involving LRP and hepatic lipase, allowing its remaining fatty acids, cholesterol, and cholesteryl esters to be transferred to the liver.

What is the first major lipoprotein formed from dietary fat?

A chylomicron containing ApoB-48 (One ApoB-48 molecule per chylomicron).

• CM are secreted by enterocytes, transporting around 90 g of dietary TG/day.

What is the role of MTP in chylomicron formation?

Microsomal triglyceride transfer protein (MTP) mediates the lipidation of ApoB-48 in enterocytes, helping form chylomicrons.

Describe the structure of chylomicrons

Chylomicrons have a core of mainly nonpolar lipids, especially triacylglycerols and cholesteryl esters (cholesterol+FA), surrounded by a monolayer of mainly polar lipids.

The outer surface contains amphipathic phospholipids and free cholesterol, along with apoproteins such as peripheral apoC and integral apoB.

How does dietary fat intake affect chylomicron size? Can the cholesterol content of chylomicrons vary?

A high-fat meal produces larger chylomicrons, while fasting produces smaller chylomicrons carrying less triglyceride.

• Yes. The amount of cholesterol carried by chylomicrons varies depending on dietary cholesterol intake.

Which apolipoproteins are on circulating chylomicrons and what are their functions?

ApoB-48: serves as the essential structural and core protein required for the assembly, stability, and secretion of chylomicrons in the small intestine

ApoC-II: Transferred from HDL to chylomicrons, ApoC-II activates lipoprotein lipase (LPL), which hydrolyzes triglycerides (TAG) in chylomicrons, releasing glycerol and fatty acids (FA). FA are then transported to the muscle/heart/adipose tissues

ApoE: Transferred from HDL to chylomicrons, ApoE helps the chylomicron remnant interact with receptors for uptake by the liver.

ApoA-1

What happens to chylomicrons after their dietary triglycerides have been delivered?

They are progressively depleted of triglyceride and ultimately disappear from circulation as their remnants are cleared.

Where is LPL synthesized, what does LPL convert triglycerides into, and what happens to fatty acids released by LPL in adipose tissue?

1. LPL is synthesized by cells in skeletal muscle, myocardium, adipose tissue, and the mammary gland, and it requires heparan sulfate proteoglycans (HSPG) on the cell surface.

2. Converts TAG into Glycerol and free fatty acids.

3. FA from LPL can be stored in adipocytes.

What happens to the fatty acids and glycerol released by LPL?

Free fatty acids can be stored in adipocytes. Glycerol is taken up by the liver, where it can support gluconeogenesis during fasting or triglyceride synthesis for VLDL production in the fed state.

What happens to a chylomicron after much of its triglyceride (and phospholipids) has been removed?

It becomes a chylomicron remnant, which can return to the liver, where its remaining fatty acids, cholesterol, and cholesteryl esters are taken up

• Chylomicron remnants can also remain in circulation, which can lead to atherosclerosis, know as spill over FAs

How can chylomicron remnants be taken up by the liver?

Through receptors including the LDL receptor, LDL receptor-related protein 1, scavenger receptor B1, and syndecan 1. Fat soluble vitamins (ADEK) and cholesterol also reach the liver.

• Uptake of CM remnant is stimulated by apoAV (working with ApoC-II), and inhibited by apoCIII.

• Delays in CM metabolism result in the transfer of CM remnants into the arterial intima. CM remnants contain more cholesterol esters and are more atherogenic.

Which lipases help convert chylomicrons into cholesterol-rich remnants?

Hepatic lipase (HL) and endothelial lipase (EL).

What factors regulate LPL activity in the enterocytes?

1. Insulin is a negative modulator of chylomicron secretion in enterocytes

   1. Insulin resistance promote chylomicron production.

   2. Insulin reduces flux of free fatty acids to the intestine, and inhibits MTP

1. CM acquire apoCII (main activator) and apoCIII (main inhibitor) of LPL, and apoE which is crucial for liver reuptake of CM remnants.

How is the insulin effect opposite in adipose vs enterocyte

• Insulin is a negative modulator of chylomicron secretion in enterocytes

• In adipocytes, insulin promotes fat storage. It supports the uptake and storage of fatty acids released from circulating chylomicrons, and it stimulates adipose-tissue handling of triglyceride-derived fatty acids.

What does chylomicrons exchange with HDL?

CM exchange peripheral proteins and lipids with HDL (key support of CM
intravascular metabolism)

Proteins: ApoC-II, ApoC-III, and ApoE.

What does the ApoC-III gene produce?

A protein of about 8 kilodaltons, which is then glycosylated in the Golgi.

What factors inhibit and increase ApoC-III production? What type of diet can increase ApoC-III production?

Inhibit: Insulin and polyunsaturated fatty acids.

Increase: Glucose, fructose, and saturated fatty acids.

• Diets very high in sugar or saturated fat increase ApoC-III

Which circulating lipoproteins are acted on by LPL?

LPL hydrolyzes triglycerides carried by ApoB-48-containing chylomicrons and ApoB-100-containing VLDL.

• It becomes a smaller, denser lipoprotein, ultimately leading to LDL formation.