Chilesterol trafficking in hepatocytes.

To secrete triglycerides and cholesterol, hepatocytes assemble VLDL particles. When lipids are available in the ER, the newly synthesized ApoB polypeptide interacts co-translationally with the microsomal triglyceride transfer protein (MTP). How MTP catalyses lipid incorporation to facilitate VLDL assembly is not fully understood. Recent results suggest that neutral lipids (cholesteryl esters and triglycerides) are not required because the phospholipid transfer activity of MTP was sufficient for the assembly and secretion of primordial ApoB lipoproteins.

Nevertheless, the addition of lipids helps the ApoB protein to fold on the forming particle and thereby escape degradation. The immature, partially lipidated VLDL particle is then secreted in COPII-coated vesicles from the ER and transported to the Golgi complex.

Figure Cholesterol trafficking in hepatocytes. Hepatocytes are the main cholesterol-synthesizing cells of the body and are thus an important target for cholesterol lowering by statins. Newly synthesized cholesterol can be delivered from the endoplasmic reticulum (ER) by Golgi bypass route(s) to other membranes. VLDL (very low density lipoprotein) and HDL (high density lipoprotein) particles are secreted through the Golgi. The assembly of VLDL particles starts in the rough ER by synthesis and co-translational translocation of the apoprotein ApoB100 (see inset). MTP (microsomal triglyceride transfer protein) transfers triglycerides and cholesteryl esters to ApoB100 co-translationally, thereby preventing its targeting to proteasomal or non-proteasomal degradation. The particles, each containing one ApoB molecule embedded in a phospholipid monolayer together with a core of triglycerides and cholesteryl esters, enter COPII vesicles in the ER. The particle receives additional lipids in the Golgi before secretion. ApoA-I, the major apoprotein of HDL, is also synthesized in the ER where it acquires some phospholipids and cholesterol, but the bulk lipidation of HDL takes place in the Golgi and plasma membrane in a process involving activity of the ATP-binding cassette (ABC) transporter ABCA1. HDL cholesterol is taken up by hepatocyte scavenger receptor B1 (SRB1) and undergoes transcytosis from the sinusoidal domain to the bile canalicular domain. The ABCG5/G8 transporter (green) at the bile canalicular surface is involved in the secretion of cholesterol into bile while NPC1L1 (Niemann–Pick C1-like-1; dark red) decreases biliary cholesterol secretion. Ezetimibe also blocks this activity of NPC1L1. Low density lipoprotein (LDL) is taken up by LDL-receptor-mediated endocytosis and Niemann–Pick C1 (NPC1)-dependent endosomal cholesterol release. Chylomicron remnants (CMR) are taken up by an ApoE-dependent process, which involves several mechanisms for particle capture and uptake, such as SRB1 and LDL receptor-related protein (LRP). The various cholesterol trafficking circuits are likely to be interconnected both at the transcriptional and post-transcriptional or post-translational levels but so far, information on this level of regulation is scanty. ACAT, acyl CoA cholesterol acyltransferase; CE, cholesteryl esters; FC, free cholesterol.

The bulk of triglycerides are added at post-ER stations, presumably in the Golgi owing to the dependence of the process on ARF1 — a GTPase that is required for Golgi trafficking events. The dynamics that are involved in further maturation of the VLDL particle to increase its lipidation remain to be elucidated. Lipid droplets may contribute to the particle growth. Furthermore, the LDL receptor and endosomal lipid processing are also involved in regulating ApoB lipidation and VLDL assembly.

Hepatocytes are also the main source of ApoA-I and HDL. Endogenously produced ApoA-I can be lipidated by both de novo synthesized and LDL-derived cholesterol, and hepatic ABCA1 is involved in the process at the level of the Golgi and plasma membrane. In striking contrast to macrophages, in hepatocytes the lack of NPC1 function is associated with increased lipidation of ApoA-I, reflecting increased ABCA1 levels.

As part of the reverse cholesterol transport process, hepatocytes take up cholesterol from HDL through the scavenger receptor SRB1. In this process, only the cholesterol and cholesteryl esters are considered to be selectively transferred into cells, whereas other lipids and apoproteins remain in the lipoprotein particle. The compartment involved in hydrolyzing sterol esters that enter through this pathway is not known but it does not involve NPC1 function. SRB1 expression correlates with biliary cholesterol secretion, but whether this depends on SRB1 activity at the canalicular membrane and/or on basolateral endocytic recycling of HDL remains open. Intriguingly, part of the mitochondrial ATP synthase complex has also been identified as a hepatocyte receptor for the uptake of entire HDL particles. The  b-chain of ATP synthase (better known as the domain that mediates nucleotide binding and hydrolysis) was found to function as an ApoA-I receptor in hepatic HDL endocytosis. Further studies are needed to address the physiological importance of this finding.

Elina Ikonen | Nature reviews | Molecular Cell Biology Volume 9 | February 2008 | p135 | www.nature.com/reviews/molcellbio