Dyslipidemia & Atherosclerosis

BCH 130 β€” Advanced Human Biochemistry Β· Dr. Radi

build Jul 18 Β· 08:24 Β· CC BY-NC-SA 4.0 Β· owned figures (RDKit / matplotlib)
Dr. Radi

By the end of this unit, you can…

  • Interpret a lipid panel (LDL-C, HDL-C, triglycerides, non-HDL, apoB) in terms of the underlying lipoprotein metabolism.
  • Explain familial hypercholesterolemia (LDL-receptor / apoB / PCSK9 defects) and its dominant biochemistry, and the major hypertriglyceridemias (LPL/apoC-II).
  • Walk the biochemistry of atherogenesis
  • Explain lipid-lowering pharmacology by target
Dr. Radi

Today's route πŸ—ΊοΈ

  1. Dyslipidemias β€” Reading the Lipid Panel
  2. Atherosclerosis β€” Pathogenesis & Drugs
Dr. Radi

1 Β· Dyslipidemias β€” Reading the Lipid Panel

"That lipid panel on the screen isn't five random numbers β€” it's a readout of lipoprotein metabolism in motion. Learn to see the particles behind the numbers, and the inherited disorders that make them go haywire, and the panel starts telling you a story."

Dr. Radi

The panel is lipoprotein metabolism

Don't read the lipid panel as five numbers β€” read it as particles. The liver ships VLDL; lipase strips its triglyceride down to cholesterol-rich LDL. Every one of those atherogenic particles carries exactly one apoB β€” so apoB counts them and non-HDL-C measures their cholesterol. LDL-C is only part of the story; HDL runs cholesterol back the other way.

Dr. Radi

Familial hypercholesterolemia

Here's a disease of a single broken step: LDL just won't leave the blood. The hepatic LDL receptor normally grabs LDL by its apoB and pulls it in. Break the receptor, break the apoB ligand, or make PCSK9 hyperactive (it degrades the receptor) β€” and clearance fails. It's autosomal dominant, so even one bad copy means sky-high LDL from birth.

Dr. Radi

When triglycerides run wild

Now the other pole. Lipoprotein lipase (LPL), anchored on the capillary wall, unloads triglyceride from chylomicrons and VLDL β€” and apoC-II is its essential on-switch. Lose either one and those fat-stuffed particles have nowhere to go: triglycerides skyrocket, and the real danger is acute pancreatitis.

Dr. Radi

The body wears its dyslipidemia

The species that accumulates literally shows up on the exam β€” the physical one! High LDL parks cholesterol in tendons and skin: tendon xanthomas, corneal arcus, xanthelasma. Stalled remnants give palmar and tuberous xanthomas. Sky-high chylomicrons bring eruptive xanthomas, milky lipemia retinalis, and pancreatitis. Read the skin, predict the particle.

Dr. Radi

2 Β· Atherosclerosis β€” Pathogenesis & Drugs

"This is where the numbers become a heart attack. Atherosclerosis is a slow, decades-long inflammatory response to lipid trapped in an artery wall β€” and once you see it built step by step, every lipid-lowering drug we reach for lands on an obvious target. Then we watch a plaque decide to kill."

Dr. Radi

Building a plaque, step by step

Atherosclerosis is an inflammatory response to trapped lipid. First the endothelium is injured β€” by LDL, smoking, glucose, high pressure. LDL slips into the intima, gets oxidized, and sounds the alarm. Monocytes pour in, become macrophages, and their scavenger receptors gorge on oxLDL into foam cells. Smooth muscle throws a fibrous cap over the mess.

Dr. Radi

Every drug hits one target

Watch how cleanly this maps. Statins block HMG-CoA reductase, so the liver makes more LDL receptors. Ezetimibe blocks NPC1L1 in the gut. PCSK9 inhibitors spare the receptor for a huge LDL drop. Bile-acid sequestrants make the liver burn cholesterol into new bile acids. Fibrates activate PPAR-Ξ± to clear triglycerides.

Dr. Radi

The plaque that kills

Here's the twist that surprises everyone: the plaque that stops your heart usually wasn't the biggest one. A stable plaque has a thick fibrous cap over a small core. A vulnerable plaque has a thin, inflamed cap over a big necrotic core β€” and when it ruptures, the thrombogenic core hits blood, a clot forms, and you get an MI or stroke in minutes.

Dr. Radi

Can you…?

  • ☐ interpret a lipid panel (LDL-C, HDL-C, triglycerides, non-HDL, apoB) in terms of the underlying lipoprotein metabolism.?
  • ☐ explain familial hypercholesterolemia (LDL-receptor / apoB / PCSK9 defects) and its dominant biochemistry, and the major hypertriglyceridemias (LPL/apoC-II).?
  • ☐ walk the biochemistry of atherogenesis?
  • ☐ explain lipid-lowering pharmacology by target?

If any box stays empty, the practice site has a drill for it. πŸ§ͺ

Dr. Radi