Are cholesterol esters primarily absorbed via the gut or as free cholesterol?

Cholesterol Absorption in the Gut: Free Cholesterol vs. Cholesterol Esters

Free cholesterol, not cholesterol esters, is primarily absorbed in the gut. Cholesterol esters must be hydrolyzed to free cholesterol before absorption can occur 1.

Mechanism of Cholesterol Absorption

Free Cholesterol Absorption

• Free cholesterol is the primary form absorbed in the intestine
• Absorption occurs via the following process:
  • Free cholesterol is incorporated into mixed micelles in the intestinal lumen
  • These micelles facilitate transport to the intestinal brush border membrane
  • Absorption occurs via the NPC1L1 protein transporter in the enterocyte membrane 2
  • Once inside enterocytes, free cholesterol has two fates:
    1. Re-esterification by ACAT2 (acyl-CoA:cholesterol acyltransferase 2)
    2. Efflux back to the intestinal lumen via ABCG5/ABCG8 transporters 1

Cholesterol Esters and Absorption

• Cholesterol esters from dietary sources cannot be directly absorbed
• They must first undergo hydrolysis to free cholesterol in the intestinal lumen
• This hydrolysis is mediated by pancreatic enzymes
• Only after conversion to free cholesterol can absorption occur 1, 3

Re-esterification and Transport

• After absorption as free cholesterol, much of the cholesterol is re-esterified within enterocytes by ACAT2
• These newly formed cholesterol esters are then:
  • Packaged into chylomicrons
  • Secreted into the lymphatic system
  • Eventually enter the bloodstream 2, 4

Selective Absorption of Cholesterol vs. Phytosterols

• An interesting comparison that highlights the specificity of this process is seen with phytosterols:
  • Phytosterols are structurally similar to cholesterol
  • However, they are poor substrates for ACAT2
  • This prevents their efficient esterification within enterocytes
  • Without esterification, they cannot be effectively packaged into chylomicrons
  • This results in minimal absorption of phytosterols (<2%) compared to cholesterol (>50%) 3

Clinical Implications

• Understanding this absorption mechanism explains why:
  • Phytosterols can displace cholesterol from micelles, reducing cholesterol absorption 5
  • Phytosterols decrease cholesterol content of micelles and hence decrease its transport towards the intestinal brush border membrane 2
  • This forms the basis for phytosterol supplementation in managing dyslipidemia 3

Transport in Circulation

• Once absorbed and packaged into chylomicrons:
  • Cholesterol esters (not free cholesterol) become the primary transport form in circulation
  • They are carried in the hydrophobic core of lipoproteins
  • This allows efficient transport of large quantities of cholesterol through the bloodstream 1, 4

Understanding this distinction between absorption (as free cholesterol) and transport (as cholesterol esters) is crucial for developing effective strategies to manage cholesterol levels and reduce cardiovascular risk.