Module 11

What backbone do phospholipids have?

Glycerol backbone

How are fatty acid chains attached to the glycerol backbone in phospholipids?

Via an ester linkage (on the bottom of the molecule)

Where is the phosphate group located in a phospholipid?

On top of the glycerol backbone

How many possible headgroups can attach to the phosphate group of a phospholipid?

5 (an amino acid, a sugar, or another organic molecule)

What backbone does sphingomyelin have?

A sphingosine backbone

How is sphingomyelin's fatty acid chain attached to its backbone?

Via an amide bond (not an ester linkage)

Why is sphingomyelin classified as a phospholipid?

Because it has a sphingosine backbone + fatty acid chain (amide bond) + phosphate group

What backbone do glycolipids/cerebrosides have?

A sphingosine backbone

What is attached to the head of a glycolipid/cerebroside?

A sugar head

Why are glycolipids/cerebrosides NOT classified as phospholipids?

Because they lack a phosphate group

What is the key structural difference between sphingomyelin and cerebrosides?

Sphingomyelin has a phosphate group (phospholipid); cerebrosides have a sugar head instead of phosphate (not a phospholipid)

In a membrane bilayer, are the outer layers hydrophilic or hydrophobic?

Hydrophilic (polar headgroups face outward)

In a membrane bilayer, is the inner layer hydrophilic or hydrophobic?

Hydrophobic (fatty acid tails face inward)

Where is cholesterol positioned within the phospholipid bilayer?

Inserted between phospholipids

Which part of cholesterol sits near the polar headgroups of phospholipids?

Its polar OH (hydroxyl) group

Which part of cholesterol sits near the fatty acid tails of phospholipids?

Its hydrophobic ring/aliphatic chain

What state is the membrane in at high temperature?

Fluid form

What state is the membrane in at low temperature?

Crystal form

What state is the membrane in at intermediate temperature?

Gel form

What is the basic structure of cholesterol?

Four fused rings attached to an aliphatic chain tail

Where is the hydroxyl (OH) group located on cholesterol?

On the first ring

Why is cholesterol described as amphipathic?

Because it has a polar OH group (hydrophilic) plus a hydrophobic ring/aliphatic tail, similar to a detergent

What role does cholesterol play in membrane stabilization?

It acts as a buffer to membrane state changes with temperature, preventing the membrane from becoming too rigid or melting

Cholesterol is a precursor to which 3 major categories of molecules?

Bile salts, vitamin D, and steroid hormones

What two molecules can conjugate with cholesterol to form bile salts?

Glycine or taurine

Besides being a precursor molecule, what other structural role does cholesterol play?

A component of lipoprotein complexes

Where does the conversion of excess cholesterol into bile salts occur?

In the liver

What chemical modification converts cholesterol into water-soluble bile salts?

Addition of OH and charged groups

Where are bile salts stored between meals?

The gallbladder

When bile salts are needed, where do they move to?

The small intestine (SI)

In the small intestine, what do bile salts link up with?

Dietary cholesterol and triacylglycerides (TAGs)

After linking with dietary fat in the SI, where do bile salts/cholesterol/TAGs travel?

Through the bloodstream back to the liver

What does the liver do with the returned fats/cholesterol from bile salt recycling?

Digests them

How are bile salts ultimately eliminated from the body?

Excreted in urine

What enzyme family mediates the conversion of cholesterol into steroid hormones?

Cytochrome P450 enzymes

What is the functional purpose of P450-mediated modification of cholesterol?

It makes cholesterol recognizable to other proteins

What is the steroid hormone pathway in the ovaries?

Cholesterol → progesterone → estradiol

What is the steroid hormone pathway in the testes?

Cholesterol → progesterone → testosterone

What is the steroid hormone pathway in the adrenal cortex?

Cholesterol → progesterone → aldosterone and cortisol

What intermediate is common to all three steroid hormone pathways (ovary, testes, adrenal cortex)?

Progesterone

What converts cholesterol to 7-dehydrocholesterol, and where?

Skin + sunlight (UV light)

After 7-dehydrocholesterol forms in the skin, where does it travel next?

The liver

What is 25-hydroxyvitamin D3 also known as?

The vitamin D precursor

After the liver produces 25-hydroxyvitamin D3, where does it travel next?

The kidney

What is the final, usable/active form of vitamin D?

1,25-dihydroxyvitamin D3

Besides skin synthesis, how else can the vitamin D precursor (25-hydroxyvitamin D3) be obtained?

From diet (ingested vitamin D that reaches the liver)

Does the ingested (dietary) form or the liver-synthesized form of the vitamin D precursor "count" toward vitamin D status?

Either form suffices

What is vitamin D primarily used for in the body?

Calcium homeostasis

What is the first committed molecule that starts cholesterol biosynthesis?

Acetyl CoA

Acetyl CoA and acetoacetyl CoA combine to form which molecule?

HMG-CoA (3-hydroxy-3-methylglutaryl-CoA)

What enzyme reduces HMG-CoA to mevalonate?

HMG-CoA reductase

What is the committed/rate-limiting step of cholesterol biosynthesis?

Conversion of HMG-CoA to mevalonate by HMG-CoA reductase

What drug class competitively inhibits HMG-CoA reductase, and what is blocked?

Statins; they block the active site of HMG-CoA reductase

What is the mnemonic for HMG-CoA reductase regulation by glucagon and insulin?

PIG DAI ("pig day")

What does glucagon do to HMG-CoA reductase (activity and phosphorylation state)?

Phosphorylates and inactivates/inhibits it → decreases cholesterol production

What does insulin do to HMG-CoA reductase (activity and phosphorylation state)?

Dephosphorylates and activates it → increases cholesterol production

Spot the swap: "Insulin phosphorylates and activates HMG-CoA reductase" — what's wrong?

Insulin DEPHOSPHORYLATES (not phosphorylates) to activate HMG-CoA reductase

Spot the swap: "Glucagon dephosphorylates and inhibits HMG-CoA reductase" — what's wrong?

Glucagon PHOSPHORYLATES (not dephosphorylates) to inhibit HMG-CoA reductase

What is the mechanism of action of statin drugs?

Competitive inhibition — they block the active site of HMG-CoA reductase

When liver cholesterol levels are too high, what 4 mechanisms halt HMG-CoA reductase activity?

1) Farnesylated proteins reduce translation, 2) Sterol regulatory elements (SREs) reduce transcription, 3) HMG-CoA reductase proteases cleave the enzyme, 4) LDL receptors are turned off

What is the mnemonic for farnesylated protein regulation of HMG-CoA reductase?

"Farnesylation, translation" — farnesylated proteins reduce HMG-CoA reductase translation

What is the mnemonic for sterol regulatory element (SRE) regulation of HMG-CoA reductase?

"Sterol scripts" — SREs reduce transcription of HMG-CoA reductase mRNA

What happens to LDL receptors when liver cholesterol is too high, and what's the downstream effect?

LDL receptors are turned off, so LDL and cholesterol are not taken up by the liver

What is the function of LDL receptors under normal conditions?

They measure circulating LDL and help with uptake of unused LDL from peripheral tissues, returning it to the liver

When liver cholesterol is too LOW, what cholesterol sensor protein becomes active?

SCAP (a cholesterol sensor)

What does SCAP do when cholesterol is low?

Brings SREBP (sterol regulatory element binding protein) from the ER to the Golgi

After SCAP brings SREBP to the Golgi, what happens next?

SREBP is cleaved and migrates to the nucleus

What does SREBP do once in the nucleus?

Binds to the SRE (sterol regulatory element) and acts on the HMG-CoA reductase gene, increasing its transcription

Summarize the low-cholesterol regulatory pathway in one sentence.

SCAP carries SREBP from ER → Golgi → nucleus, where it binds SRE and upregulates HMG-CoA reductase transcription

What are lipoprotein complexes and where are they synthesized?

Complexes that carry cholesterol, cholesterol esters, and triacylglycerides; synthesized in the liver

In a lipoprotein complex, what is on the hydrophilic outside?

Cholesterol

In a lipoprotein complex, what is packed in the hydrophobic inside?

Cholesterol esters and triglycerides

What is the function of apolipoproteins on the surface of lipoproteins?

They mediate cell signaling

What do chylomicrons transport, and along what route?

Dietary triacylglycerides (TAG) and cholesterol, from the small intestine to the liver/tissues

What does "chyle" mean?

Milky digestive fluid from the intestines

What does VLDL transport, and where does it go?

TAG synthesized in the liver (from diet) → to adipose tissue for storage

What pathway do chylomicrons and VLDL both belong to?

The dietary (TAG transport) pathway

What does LDL carry, and in which direction?

Cholesterol synthesized in the liver → to tissues; if cholesterol isn't needed, LDL brings it back to the liver

What does HDL carry, and in which direction?

Cholesterol from peripheral tissues → back to the liver (scavenger function)

What additional cardiovascular benefit does HDL provide?

Helps mitigate clotting

What pathway do LDL and HDL both belong to?

The biosynthetic (overflow cholesterol transport) pathway

What is IDL?

A transient lipoprotein form between VLDL and LDL

Is there truly a "good" and "bad" cholesterol?

No — there is no inherently good or bad cholesterol (LDL/HDL differ in transport direction, not in cholesterol quality)

Summarize how the liver controls cholesterol biosynthesis via bile salts.

Excess cholesterol → converted to bile salts in liver → stored in gallbladder → released to SI to digest fat/TAG → recycled back to liver → liver digests fats → salts excreted

What event initiates atherosclerosis/cardiovascular disease?

A microtear in the vessel wall triggers an inflammatory response

What binds to a vessel microtear during plaque formation?

Mutated or damaged apolipoproteins on the LDL surface

What deposits onto the tear after damaged LDL apolipoproteins bind?

TAGs and cholesterol from LDL

Under what LDL:HDL ratio condition does plaque form and clog vessels?

When LDL > HDL (insufficient cholesterol scavenging by HDL)

Name 5 factors that worsen/exacerbate cardiovascular disease progression.

High blood pressure/coronary artery stress, collagen or elastin defects, overactive immune response to microtearing, free radicals (e.g., hydrogen peroxide, homocysteine), and TMAO

How do free radicals like hydrogen peroxide and homocysteine contribute to plaque formation?

They damage LDL/apolipoproteins, which then travel to the microtear site and spill their contents

What is TMAO and how does it affect cardiovascular risk?

A bacterial byproduct made in the small intestine that increases LDL and reduces HDL scavenging

What dietary change helps decrease inflammation for cardiovascular health?

Decrease trans fat and omega-6 intake

What dietary change helps increase HDL for cardiovascular health?

Increase essential fatty acid/omega-3 intake

How does exercise affect LDL and HDL levels?

Increases HDL (scavenger) and decreases LDL (depositor)