HMG-CoA reductase. Statins. LDL receptors. Five fates. The engine that runs your membranes and kills your vessels.
Start the chain ↓Six metabolites. One linear pathway. Tap to drop each into the next slot until the chain reads Acetyl-CoA → cholesterol. Statins hit step 2 · once you order it, you own the drug target.
A 42-year-old man with a strong family history of heart disease has a total cholesterol of 310 mg/dL. He is started on atorvastatin. Four weeks later, his LDL has dropped 45%. The PRIMARY mechanism behind this LDL reduction is:
This is the classic trap. People say "statins lower LDL." True. But HOW? The liver is the key. Understanding why LDL drops requires you to trace the chain from enzyme inhibition all the way to receptor upregulation. That chain is what this page builds.
Memory Hooks · Tap to unblur. The dumber the hook, the better it sticks.
Cholesterol synthesis runs on acetyl-CoA. Three steps get you to HMG-CoA, then one committed step gets you to cholesterol. Hover each node for detail. The rate-limiting enzyme is HMG-CoA reductaseThink of this as the factory manager of cholesterol production in the liver. Statins are the layoff notice. No manager, no output, LDL drops., the statin target.
HMG-CoA Reductase is the master switch. It runs on a timer and responds to feedback:
Low cholesterol activates SREBP-2, which increases transcription of HMG-CoA Reductase. Insulin dephosphorylates/activates it. AMPK (fasting/exercise) phosphorylates/inactivates it.
Regulation is transcriptional (SREBP-2) + post-translational (AMPK). Not allosteric by substrate.
Dietary cholesterol inhibits HMG-CoA Reductase. Product feedback: "we already have enough, stop."
Classic negative feedback loop. Eats a steak, liver slows synthesis.
HMG-CoA Reductase is most active at 8 PM. That's why statins given at night work better (except atorvastatin/rosuvastatin, which have long half-lives).
Take simvastatin/pravastatin at bedtime for maximal effect.
The pathway has one bottleneck and one therapeutic chokepoint · HMG-CoA reductase. It turns HMG-CoA into mevalonate, which becomes IPP, then farnesyl, then squalene, then cholesterol. Statins block this step; cell senses low intracellular cholesterol → upregulates LDL receptors → pulls more LDL out of plasma. That's the whole reason statins lower LDL · it's not direct, it's by receptor upregulation. The pathway also feeds 5 fates · cholesterol, bile acids, steroid hormones, vitamin D, and ubiquinone. Block reductase → you can affect all five (rare myopathy from CoQ10 depletion is the clinical medicine lore).
Once synthesized, cholesterol has five places to go. Click each card to expand the detail.
Fat doesn't dissolve in blood. Lipoproteins are the delivery trucks. Know your vehicles, their cargo, and their route.
| Lipoprotein | Origin | Primary Cargo | Key Apolipoprotein | Function |
|---|---|---|---|---|
| Chylomicron | GI tract (intestine) | Dietary triglycerides (85-88%) | ApoB-48, ApoE, ApoCII | Delivers dietary fat to peripheral tissues via lipoprotein lipase |
| VLDL | Liver | Triglycerides (~95%) | ApoB-100, ApoCII, ApoE | Delivers hepatic TGs to peripheral tissues; becomes IDL then LDL |
| IDL | VLDL remnant | Cholesterol + TGs | ApoB-100, ApoE | Intermediate; taken up by liver or converted to LDL |
| LDL | IDL (VLDL remnant) | Cholesterol (~50%) | ApoB-100 only | Delivers cholesterol to peripheral cells; taken up by LDLR via clathrin pits |
| HDL | Liver + Intestine | Cholesterol (reverse transport) | ApoA-I | Reverse cholesterol transport: peripheral → liver. Cardioprotective. |
LDL circulates carrying ApoB-100. Cells needing cholesterol express the LDL Receptor (LDLR). When LDL-ApoB-100 binds LDLR, the complex clusters in clathrin-coated pitsClathrin is a cage protein that pinches off membrane vesicles. LDL-receptor complexes cluster in these coated pits, get pinched inward, and delivered to lysosomes for degradation. Classic receptor-mediated endocytosis. and is endocytosed. Inside the lysosome, LDL is degraded; cholesterol is released for use. The receptor recycles back to the surface.
Clathrin pits = marker for LDL receptor activity
HDL scavenges cholesterol from peripheral tissues and arterial plaques. Delivers it back to the liver (reverse cholesterol transport). ApoA-I activates LCAT to esterify cholesterol. High HDL = protective.
Think of HDL as the cleanup crew after the LDL delivery trucks have dumped their load.
Lipoprotein math, simplified. Chylomicrons = dietary TG, from gut (ApoB-48). VLDL = liver TG export. IDL = VLDL with TG removed. LDL = cholesterol delivery to peripheral tissue (ApoB-100 docks to LDL receptor). HDL = reverse cholesterol transport from periphery to liver (ApoA-I). LPL on capillary endothelium chews TG off chylo and VLDL; Hepatic lipase finishes the VLDL → IDL → LDL conversion. Familial hypercholesterolemia = broken LDL receptor → LDL can't get into cells → piles in plasma → xanthomas, tendon thickening, early MI.
Statins are competitive inhibitors of HMG-CoA Reductase. Use the simulator below to see the cascade of effects as you increase statin dose.
Adjust dose or select a statin to see real-time changes in hepatic synthesis, LDL receptor expression, and serum LDL. This models the pharmacodynamic cascade.
| Statin | Key Board Fact | Route of Excretion | Potency |
|---|---|---|---|
| Simvastatin | Mortality benefit in diabetes | Hepatic/fecal | Moderate |
| Atorvastatin | First-line for males with family history; long half-life, take any time | Hepatic/fecal | High |
| Pravastatin | Renal excretion: use in liver disease; fewer drug interactions | Renal | Moderate |
| Rosuvastatin | Most potent; largest LDL reduction; take any time | Hepatic/fecal | Very High |
Hypercholesterolemia shows up on the body before it shows up on angiography. Know the external signs.
Tendon xanthomas: yellow-orange fat deposits on extensor tendons, especially the Achilles tendon and elbow. Pathognomonic for Familial Hypercholesterolemia (FH). Made of cholesterol-laden macrophages (foam cells).
Board shortcut: Xanthoma on Achilles or elbow = think LDL receptor mutation.
Yellow plaques on eyelids (periorbital). Associated with elevated LDL / hypercholesterolemia. Can occur with normal lipids, but in clinical practice = cholesterol problem.
Xanthelasma = eyelids = LDL/cholesterol. Xanthoma = tendons = LDL/FH. Eruptive xanthomas = trunk/extensor surfaces = high triglycerides.
White/grey ring around the cornea from cholesterol deposits. In people over 50: normal aging finding. In people under 40: pathologic sign of hypercholesterolemia, especially FH.
Age matters: young + arcus = alarming. Old + arcus = meh.
Familial Hypercholesterolemia (FH) is an autosomal dominant mutation in the LDL Receptor gene. The LDLR cannot bind ApoB-100 properly, so LDL cannot be cleared from blood.
5 questions per load. Shuffled every time. Wrong-answer explanations walk you through the mechanism and clarify what to do next.
Cholesterol quiz patterns to expect: (1) "Best treatment to lower LDL" → statin (HMG-CoA reductase inhibitor). (2) "Statin side effect" → myopathy (worse with fibrates), hepatitis (LFTs), rare rhabdo. (3) "Mechanism of statin LDL-lowering" → upregulates hepatic LDL receptors (NOT direct synthesis block at LDL). (4) "Bile acid sequestrant" → cholestyramine, depletes bile acids → liver makes more from cholesterol → LDL down (but raises TG). (5) "PCSK9 inhibitor" → prevents LDL receptor degradation → more receptors stay on hepatocyte surface. Match the drug to the pathway step, not the lab number.
Tap a card to flip it.
Pick a lipid abnormality to trace the treatment path.
