The road to statins runs through mouse experiments, Nobel Prize–winning biochemistry, thousands of fungal cultures, and a discovery that nearly never reached patients.

In this episode of Mechanism of Action, we continue our cholesterol series with the story of Akira Endo, a Japanese scientist whose fascination with mushrooms and molds helped launch a new era of cholesterol treatment. Inspired by the discovery of penicillin, Endo searched the fungal world for something that could block the body’s cholesterol production.

We trace the science from acetate and the cholesterol synthesis pathway to HMG-CoA reductase—the enzyme that became statins’ target. Along the way, we explore the discovery of compactin, disappointing animal experiments, safety concerns that threatened the entire field, and the eventual arrival of lovastatin.

• (00:00:00) - Cholesterol Synthesis and the Road to Statins
• (00:01:18) - Mouse Experiments Reveal Cholesterol Regulation
• (00:02:43) - Mapping the Cholesterol Synthesis Pathway
• (00:05:45) - Nobel Prizes and a Promising Drug Target
• (00:08:07) - Akira Endo’s Fascination with Fungi
• (00:09:51) - Searching Thousands of Fungal Strains
• (00:11:07) - Compactin and the Rat Experiment Setback
• (00:13:20) - Testing Compactin in Patients
• (00:14:15) - Safety Concerns Halt Development
• (00:15:45) - Merck, Lovastatin, and the First Approved Statin
• (00:17:13) - Proving Statins Could Save Lives
• (00:18:19) - The Discoveries That Changed Cholesterol Treatment

A failed schizophrenia treatment, a vitamin given in massive doses, radioactive rats, and a water-filter resin that became one of the first drugs used to lower cholesterol.

In this episode, we trace the strange early history of cholesterol-lowering therapy through niacin and cholestyramine. We begin in a Saskatchewan psychiatric hospital, where researchers experimenting with high-dose niacin as a treatment for schizophrenia stumbled onto an unexpected effect: cholesterol levels fell. That observation helped launch niacin into cardiovascular medicine and eventually contributed to some of the earliest evidence that lowering cholesterol could reduce the risk of heart attack.

From there, we follow radioactive cholesterol through laboratory rats as scientists worked out how the body eliminates—and then reabsorbs—cholesterol through the liver, bile, and intestines. That discovery opened the door to an entirely different approach: preventing bile acids from being recycled.

The solution came from an unlikely place: ion-exchange resins already used in water treatment. Cholestyramine could trap bile acids inside the intestine and force the body to use more cholesterol to replace them. Together, niacin and cholestyramine helped establish a revolutionary idea that cholesterol wasn't just associated with heart disease, but could be deliberately lowered to reduce cardiovascular risk—setting the stage for the statin era that followed.

• (00:00:00) - Niacin, Cholestyramine, and a Saskatchewan Schizophrenia Case
• (00:03:26) - What Is Niacin? The Story of Pellagra
• (00:06:51) - Black Tongue Reveals Niacin
• (00:07:36) - Why Niacin Was Tried for Schizophrenia
• (00:08:59) - Altschul’s Cholesterol Experiments
• (00:10:42) - The Coronary Drug Project
• (00:12:51) - Following Radioactive Cholesterol
• (00:14:11) - Siperstein and Chaikoff’s Rat Experiments
• (00:16:36) - Discovering Cholesterol Recycling
• (00:18:09) - How Cholestyramine Traps Bile Acids
• (00:19:37) - The First Human Cholestyramine Study
• (00:20:23) - A Trial Tests Heart Attack Prevention
• (00:21:31) - Why Cholestyramine Was Hard to Take
• (00:22:53) - When Doctors Began Treating Cholesterol
• (00:24:47) - Next: Statins

An eleven-year-old girl, cholesterol-fed rabbits, a wartime centrifuge, and the receptors that transformed our understanding of heart disease.

In this episode, we trace how scientists uncovered the connection between cholesterol and atherosclerosis. We begin with an 1889 case involving a young girl covered in xanthomas, then follow cholesterol from its discovery in bile to the fatty plaques found inside diseased arteries.

From there, we explore the experiments that showed cholesterol could cause atherosclerosis, the technology that separated HDL from LDL, and the families whose early heart disease revealed the genetics of familial hypercholesterolemia. Finally, we examine the discovery of the LDL receptor and how it transformed our understanding of cholesterol metabolism laying the foundation for modern cholesterol-lowering therapies.

• (00:00:00) - Cholesterol: Xanthomas, Blood, and Bile
• (00:01:07) - The First Case of Familial Hypercholesterolemia
• (00:02:49) - What Is Cholesterol?
• (00:03:54) - From Hardening Arteries to Atherosclerosis
• (00:04:47) - Cholesterol’s Discovery in Bile
• (00:08:04) - Finding Cholesterol in Arterial Plaques
• (00:11:12) - Proving the Connection with Rabbits
• (00:14:25) - High Cholesterol Runs in Families
• (00:15:47) - Cholesterol Is More Than One Thing
• (00:17:37) - Discovering HDL and LDL
• (00:19:01) - Connecting LDL to Heart Disease
• (00:21:41) - The Discovery of the LDL Receptor