Cholesterol trafficking in enterocytes

Within the lumen of the intestine, micellar solubilization of dietary sterols by bile acids helps them to move through the diffusion barrier of the absorptive cells, enterocytes. Plant sterols and stanols have a higher affinity to the bile salt micelles than cholesterol, and by displacing cholesterol in micelles, they decrease its absorption. Hence, increased consumption of dietary plant sterols or stanols can be used as a cholesterol-lowering strategy. The ABCG5/G8 transporter functions at the apical membrane of enterocytes to export absorbed cholesterol and plant sterols from enterocytes into the lumen of the gut.

Figure Cholesterol trafficking in enterocytes. Micellar solubilization of dietary sterols by bile acids allows them to move through the diffusion barrier overlying the luminal surface of enterocytes. The NPC1L1 (Niemann–Pick C1-like-1) protein (dark red) is located at the apical membrane of enterocytes and facilitates the uptake of cholesterol across the brush border membrane. This is blocked by the cholesterol absorption inhibitor ezetimibe. In contrast, the ABCG5/G8 transporter (green) promotes the active transfer of cholesterol and plant sterols back into the intestinal lumen for excretion.

Acyl CoA cholesterol acyltransferase isoform-2 (ACAT2) esterifies the absorbed cholesterol, which becomes incorporated into nascent chylomicron particles. How the absorbed cholesterol reaches ACAT2 is not known. Chylomicrons are synthesized around the APOB48 apoprotein in the endoplasmic reticulum (ER). Dietary fatty acids are used for triglyceride synthesis in the smooth ER and MTP (microsomal triglyceride transfer protein) transfers triglycerides and cholesteryl esters to APOB48. The nascent chylomicrons leave the ER in COPII-coated vesicles and are secreted through the Golgi complex to the basolateral side of the enterocyte and reach the venous circulation through lymphatic vessels.

Furthermore, the Niemann–Pick C1-like-1 (NPC1L1) protein, which is found in the apical membrane of enterocytes, may actively facilitate the uptake of cholesterol by promoting the passage of sterols across the brush border membrane. NPC1L1 is structurally homologous to NPC1 and includes an SSD, but its expression is restricted to the small intestine and the liver whereas NPC1 is ubiquitously expressed. As for NPC1, the precise mechanism of cholesterol transfer by NPC1L1 is not known but the protein is localized to the apical domain of enterocytes, and several lines of evidence implicate NPC1L1 as the target of the cholesterol absorption inhibitor ezetimibe. How the absorbed cholesterol is transported in enterocytes to reach the site of chylomicron assembly in the ER is essentially unknown. NPC1L1 may be functionally linked to NPC1 in some species such as D. melanogaster, in which the NPC1 orthologue influences cholesterol uptake. However, in mice, neither NPC1 nor NPC2 appears to have a role in intestinal cholesterol absorption. Clearly, searches for additional proteins that are involved in intra-enterocyte sterol absorption are justified, not least because of their potential as targets for limiting dietary cholesterol uptake.

A short variant of APOB, APOB48, is used as the apoprotein for packaging absorbed lipids to form chylomicrons in enterocytes. In the ER of enterocytes, cholesterol becomes esterified by the ACAT2 enzyme and the particle is secreted from the ER in COPII-coated vesicles to reach the lymphatic vessels at the basolateral side of the epithelium.

Elina Ikonen | Nature reviews | Molecular Cell Biology Volume 9 | February 2008 | p134 | www.nature.com/reviews/molcellbio