BMSC 230 Module 10: Synthesis and Transport of Triacylglycerol, Phospholipids, and Cholesterol

Lipid synthesis focuses on three primary classes: triacylglycerol (the fatty acid storage form), phospholipids (membrane components), and cholesterol.
Cholesterol serves as a structural component of membranes and a precursor for steroid hormones, bile salts, and vitamin D.
Phosphatidate is the central precursor for both triacylglycerol and phospholipids.

Triacylglycerols and phospholipids both possess a $3$ -carbon glycerol backbone.
Triacylglycerols have three fatty acids linked to the glycerol; phospholipids have two fatty acids at carbons $1$ and $2$ , with a phosphate group and a head group at carbon $3$ .
$\text{Glycerol-3-P}$ is a common precursor derived from dihydroxyacetone phosphate in the liver or via phosphorylation of glycerol (catalyzed by an enzyme present only in the liver).
$\text{Phosphatidate}$ synthesis involves two consecutive additions of fatty acids from an acyl-CoA derivative to carbon $1$ (typically saturated) and carbon $2$ (typically unsaturated) of $\text{Glycerol-3-P}$ .
Triacylglycerol is synthesized on the ER membrane in two steps: the phosphate group is removed from phosphatidate to form diacylglycerol (DAG), followed by the addition of a third fatty acid.

Phospholipid synthesis requires activated precursors, typically using cytidine diphosphate (CDP).
In yeast and bacteria, diacylglycerol is activated: phosphatidate reacts with CTP to form $\text{CDP-diacylglycerol}$ , which then reacts with an alcohol to release CMP.
In mammals, the alcohol (such as choline) is activated: choline is phosphorylated to phosphocholine and then converted to $\text{CDP-choline}$ using CTP. This is the rate-limiting step.
$\text{Phosphatidylcholine (PC)}$ is the most abundant animal phospholipid, comprising $50\%$ of membrane mass.
An alternative liver pathway for PC synthesis involves the triple methylation of $\text{phosphatidylethanolamine (PE)}$ using $\text{S-adenosylmethionine (SAM)}$ as the methyl donor.

All $27$ carbons of cholesterol are derived from $\text{acetyl CoA}$ .
Synthesis occurs in four stages, moving from the cytosol to the ER:
- Stage 1: Synthesis of mevalonate from $3$ $\text{acetyl CoA}$ molecules. The committed and regulated step is the reduction of $\text{HMG-CoA}$ to mevalonate by $\text{HMG-CoA reductase}$ , which uses $2$ $\text{NADPH}$ .
- Stage 2: Multi-step conversion of mevalonate into an activated isoprene molecule.
- Stage 3: Synthesis of squalene from six isoprene units.
- Stage 4: Cyclization of squalene to form the fused ring structure of cholesterol.

Hydrophobic lipids are transported through the blood in lipoprotein particles consisting of a hydrophobic core and a hydrophilic shell containing proteins (apoproteins).
Chylomicrons: Formed in the small intestine to transport dietary triacylglycerol.
VLDL (Very Low Density Lipoprotein): Produced in the liver to transport endogenous triacylglycerol to muscle or adipose tissue.
IDL (Intermediate Density Lipoprotein): Formed as VLDL loses triacylglycerols; partly taken up by the liver and partly converted to LDL.
LDL (Low Density Lipoprotein): The main transport vehicle for cholesterol, delivering it to peripheral cells via the LDL receptor through endocytosis. Cholesterol is stored as cholesterol esters (e.g., $\text{cholesteryl stearate}$ ).
HDL (High Density Lipoprotein): Facilitates reverse cholesterol transport, picking up excess cholesterol from the blood/tissues and returning it to the liver.
Familial Hypercholesterolemia: A genetic disease caused by LDL receptor defects, leading to dangerously high blood cholesterol levels and increased risk of coronary heart disease.

Cholesterol ( $C_{27}$ ) is the precursor for progestagens ( $C_{21}$ ), glucocorticoids ( $C_{21}$ ), mineralocorticoids ( $C_{21}$ ), androgens ( $C_{19}$ ), and estrogens ( $C_{18}$ ).
Mineralocorticoids (e.g., aldosterone) regulate blood pressure and salt balance; glucocorticoids (e.g., cortisol) regulate metabolism and inhibit inflammation.
Testosterone exhibits both anabolic activity (muscle growth) and androgenic activity (male characteristics).
Anabolic steroids like $\text{Stanozolol}$ and $\text{tetrahydrogestrinone}$ ("The Clear") are used illicitly to enhance performance at doses often $100\times$ the clinical standard.

Which statement about phosphatidylcholine is CORRECT? It can be synthesized by multiple methylations of phosphatidylethanolamine.
What molecule serves as the building block for cholesterol synthesis? Acetyl CoA.
How do statins lower plasma cholesterol levels? They inhibit the cholesterol synthetic pathway.
What do phospholipids and triacylglycerol have in common? They both have a glycerol backbone.
Which biomolecule provides the reducing equivalents needed for cholesterol synthesis? NADPH.
What is the primary role of LDLs? To deliver cholesterol to tissues.
What is the main regulatory enzyme of cholesterol synthesis? HMG-CoA reductase.
Fatty acids are linked to glycerol through what type of bond? Ester bonds.