BICH 411 exam 3

to process insoluble dietary triacylglycerols (TAGs) into fatty acids and glycerol for absorption by the intestinal mucosa and subsequent transport to tissues for energy production or storage

what is the purpose of lipid digestion, absorption, and transport?

• triacylglycerols (90%)

• cholesterol

• cholesterol esters

• phospholipids

• fat soluble vitamins (KADE)

what are the major dietary lipids?

lipids are water insoluble (hydrophobic), whereas digestive enzymes operate in an aqueous (soluble) environment, necessitating emulsification to facilitate interaction

why is lipid digestion more difficult than carb digestion?

small intestine

where is the primary site of lipid digestion?

Bile salts emulsify fats in the small intestine, increasing surface area for lipase digestion and aiding lipid absorption. They are amphipathic because they have both a hydrophobic (fat-interacting) side and a hydrophilic (water-interacting) side, allowing them to disperse fat in an aqueous environment

what is the function of bile salts/acids, and why are they amphipathic?

Bile is synthesized in the liver when hepatocytes convert cholesterol into bile acids, which are then conjugated to form bile salts. These are secreted into bile along with phospholipids, cholesterol, and bilirubin. Bile flows through bile ducts to the gallbladder, where it is stored and concentrated until needed for fat digestion in the small intestine.

how is bile synthesized in the liver and stored in the gallbladder?

The process of breaking up large fat droplets into smaller emulsion droplets; to increase the surface area available for lipase activity

what is emulsification and why is it important for lipid digestion?

Micelles form when bile salts surround lipid digestion products (fatty acids, monoglycerides), with hydrophobic parts inward and hydrophilic parts outward. This keeps lipids soluble in the intestinal fluid and transports them to the intestinal cells for absorption.

how is micelle formation done and why is it important in lipid digestion?

it anchors pancreatic lipase to the lipid-water interface; interfacial activation then triggers a structural change in PL to access its active site
this overcomes bile salt inhibition and enables lipase to access and digest the hydrophobic core of fats.

what is the function of colipase and its importance in enabling pancreatic lipase?

Cholesterol esterase and phospholipase A₂ (less important than pancreatic lipase).

Which pancreatic enzymes assist lipid digestion besides pancreatic lipase?

Only free fatty acids (FFAs) and monoacylglycerols (MAGs); TAGs and DAGs must be hydrolyzed first.

Which lipid forms are absorbed in the intestine?

Reabsorbed in the distal small intestine for recycling (enterohepatic circulation) or excreted.

What happens to bile after lipid digestion?

Binds fatty acids inside intestinal cells to keep them soluble and transport them intracellularly.

What is the role of fatty acid-binding protein (FABP)?

Fatty acids → reesterified to TAGs
Cholesterol → reesterified to cholesterol esters
all then packaged with apoproteins → chylomicrons

What happens to lipids inside intestinal mucosal cells?

They are too large to enter blood capillaries directly.

Why do chylomicrons enter lymph before blood?

Exogenous = dietary (from intestine/chylomicrons)
Endogenous = synthesized in liver or stored in adipose tissue

What is the difference between exogenous and endogenous lipids?

Core: TAGs + cholesteryl esters
Surface: phospholipids + cholesterol + apoproteins

What is the general structure of lipoproteins?

 Intestine (exogenous) → Peripheral tissues → Liver

chylomicron path

 Primarily TAGs + other dietary lipids; ApoB-48 (structural), ApoC-II (activates LPL), and ApoE (receptor ligand)

chylomicron composition

• Transports dietary TAGs absorbed from the intestine to muscle & adipose tissue for energy use or storage

  • Delivers remnants to the liver for processing

chylomicron major roles

Liver (endogenous) → Peripheral tissues

VLDL path

Mostly TAGs + some cholesterol; ApoB-100 (structural), ApoC-II (activates LPL), and ApoE (receptor ligand)

VLDL composition

•  Delivers endogenously synthesized TAGs from the liver to muscle and adipose tissue

  • Provides energy storage molecules made by the liver

  • Serves as the precursor to IDL and LDL particles in circulation

  • Starting point for endogenous lipid transport for TAG delivery from liver to tissues

VLDL major roles

• Circulates between tissues and liver; Formed in circulation after VLDL loses TAGs through LPL activity

IDL path

Mixture of TAGs and cholesterol; ApoB-100 (structural) and ApoE (receptor ligand)

IDL composition

• Transitional carrier between VLDL and LDL

  • ~50% returns partially depleted TAGs and cholesterol to the liver

  • ~50% converts to LDL after additional TAG removal

IDL major roles

Produced from IDL after removal of remaining TAGs by hepatic lipase

LDL path

Mostly cholesterol, minimal TAG; ApoB-100 (structural and receptor ligand).

LDL composition

• Transports cholesterol to peripheral cells for membrane synthesis, steroid production, and storage

  • Major cholesterol carrier in blood

  • High plasma LDL levels promote atherosclerosis and cardiovascular disease → “bad cholesterol”

LDL major roles

Peripheral tissues → Liver; Synthesized in the liver and as small nascent discoidal particles with ApoA-I

HDL path

Mostly cholesterol & proteins; ApoA-I (activator of LCAT & ABC transporters)

HDL composition

• Collects excess cholesterol from cells and transports it to the liver for excretion or recycling

  • Protective role against cardiovascular disease

  • Associated with “good cholesterol” due to its ability to remove cholesterol from arteries

HDL major roles

exogenous TAGs; small intestine

what do chylomicrons carry and where do they come from?

endogenous TAGs; liver

what do VLDL carry and where do they come from?

cholesterol; formed in blood (result of VLDL metabolism)

what do LDL carry and where do they come from?

cholesterol and phospholipids; liver and small intestine

what do HDL carry and where do they come from?

Density ↑ as protein content ↑

How does lipoprotein density change?

ApoA-I

 Activates LCAT; enables HDL to bind liver SR-BI receptor; mediates reverse cholesterol transport via ABCA1 and ABCG1 transporters; major structural component of HDL.

ApoB-100

• Only apolipoprotein found in LDL; Binds to LDL receptor for clathrin-coated endocytosis of LDL particles into peripheral tissues. Present on VLDL & IDL because they are both precursors for LDL.

ApoE

Binds to LDL receptors to enable entry into liver

ApoC-II

Activates lipoprotein lipase (TAG hydrolysis) in circulation.

Hydrolyzes TAGs in circulating lipoproteins → releases fatty acids

What does lipoprotein lipase (LPL) do?

muscle cells oxidize them for fuel, while adipocytes reesterify them for storage as TAGs

What happens to fatty acids in muscle vs adipose?

Transports free fatty acids in the blood

What is the role of albumin in lipid transport?

During fasting or stress (low insulin, high glucagon/epinephrine)

When do adipocytes release fatty acids?

Glucagon and epinephrine

What hormones stimulate lipolysis?

cAMP → PKA → activates hormone-sensitive lipase (HSL)—mobilizes stored TAGs into free fatty acids and glycerol

What pathway activates lipolysis?

Breaks down stored TAGs in adipose tissue

What does hormone-sensitive lipase (HSL) do?

Sent to liver for gluconeogenesis

What happens to glycerol released from adipose?

Facilitates fatty acid uptake into cells

What is the role of CD36?

Activated to fatty acyl-CoA by acyl-CoA synthetase

What must happen before fatty acids are oxidized?

2 ATP equivalents (ATP → AMP + PPi)

What is the energy cost of fatty acid activation?

Drives the activation reaction forward

Why is PPi hydrolysis important?

Long-chain: ER or outer mitochondrial membrane
Short/medium-chain: mitochondria

Where does fatty acid activation occur?

Inability to oxidize medium-chain fatty acids → hypoglycemia and low energy during fasting

What is MCAD deficiency?

Transports long-chain fatty acyl-CoA into the mitochondrial matrix for β-oxidation

Why is carnitine needed?

Breaks down fatty acids to generate acetyl-CoA, NADH, and FADH₂ for ATP production.

What is the purpose of β-oxidation?

Mitochondrial matrix

Where does β-oxidation occur?

Fatty acids are broken down by removing 2-carbon units as acetyl-CoA.

What happens during β-oxidation?

The β-carbon is oxidized during the process.

Why is it called β-oxidation?

1. Oxidation

2. Hydration

3. Oxidation

4. Thiolysis

What are the 4 steps of β-oxidation?

Acyl-CoA dehydrogenase
Enoyl-CoA hydratase
3-L-hydroxyacyl-CoA dehydrogenase
β-ketoacyl-CoA thiolase

What enzymes are involved in β-oxidation?

the oxidation of fatty acyl-CoA to create a trans-double bond between C2 and C3 (trans-Δ2-enoyl-CoA).

• Cofactor/Yield: Uses FAD to produce FADH2​. Electrons pass through electron transfer flavoprotein (ETF), bypassing complexes I and II

what rxn does acyl coA dehydrogenase catalyze?

Adds water across the newly created double bond to form 3-L-hydroxyacyl-CoA

what rxn does enoyl coA hydratase catalyze?

Oxidizes the hydroxyl group into a ketone to form β-ketoacyl-CoA.

• Cofactor/Yield: Uses NAD+ to produce NADH

what rxn does 3-L-hydroxyacyl-CoA dehydrogenase catalyze?

Cleaves the bond between C2 and C3 using the thiol group of a second Coenzyme A.

• Products: Generates one acetyl-CoA and a fatty acyl-CoA shortened by 2 carbons

what rxn does β-ketoacyl-CoA thiolase (thiolase) catalyze?

1 FADH₂, 1 NADH, 1 acetyl-CoA, and a fatty acyl-CoA shortened by 2 carbons

What is produced per round of β-oxidation?

FADH₂ = 1.5 ATP
NADH = 2.5 ATP

What is the ATP yield per round of β-oxidation?

2 ATP equivalents

What is the cost of fatty acid activation?

They are more reduced (more electrons → more NADH/FADH₂ → more ATP).

Why do fatty acids yield more energy than carbohydrates?

Electrons go to ETF and bypass Complex I.

Why does FADH₂ from β-oxidation yield only 1.5 ATP?

Extra enzymes are needed and some steps skip FADH₂ production or use NADPH.

Why do unsaturated fatty acids yield less ATP?

2,3-enoyl-CoA isomerase

What enzyme fixes most cis double bonds?

Loss of 1.5 ATP (no FADH₂ formed)

What is the energy penalty for skipping acyl-CoA dehydrogenase?

2,4-dienoyl-CoA reductase

What enzyme requires NADPH and fixes conjugated double bonds?

~2.5 ATP equivalent

What is the energy cost of using NADPH?

Propionyl-CoA (3 carbons)

What is the final product of odd-chain fatty acid oxidation?

Propionyl-CoA carboxylase → Methylmalonyl-CoA epimerase → Methylmalonyl-CoA mutase

How is propionyl-CoA converted to succinyl-CoA?

Biotin (carboxylase) and vitamin B₁₂ (mutase)

What cofactors are required for this conversion?

They form succinyl-CoA, which can enter gluconeogenesis.

Why are odd-chain fatty acids glucogenic?

Break down very long-chain and branched fatty acids.

What is the role of peroxisomes in fatty acid oxidation?

Uses acyl-CoA oxidase instead of dehydrogenase.

What is different about the first step in peroxisomes?

Transferred to O₂ → forms H₂O₂ (no ATP produced)

What happens to electrons in peroxisomes?

catalase

What enzyme detoxifies H₂O₂?

FADH₂ electrons do not enter the ETC.

Why does peroxisomal oxidation yield less ATP?

Provide a transportable form of acetyl-CoA for energy.

What is the purpose of ketone bodies?

Acetoacetate, β-hydroxybutyrate, acetone

What are the three ketone bodies?

Lacks 3-ketoacyl-CoA transferase

Why can’t the liver use ketone bodies?

Fasting, low carbs, high β-oxidation

When does ketone production increase?

Reverse of the last step of β-oxidation

What is the first step of ketogenesis?

HMG-CoA lyase

What is the committed step of ketogenesis?

Export, → β-hydroxybutyrate, → acetone

What are the fates of acetoacetate?

High NADH levels

What determines β-hydroxybutyrate formation?

Monocarboxylate transporters (MCTs)

How do ketone bodies enter cells?

Converted to acetyl-CoA → enters TCA cycle

How are ketone bodies used for energy?

Uses succinyl-CoA instead of ATP

What is unique about acetoacetate activation?

Loss of 1 ATP equivalent (no GTP formed)

What is the energy consequence of acetoacetate activation?

Provide energy and spare glucose and protein.

Why are ketone bodies important during fasting?

Serve as an alternative fuel when glucose is low.

Why are ketone bodies important for the brain?