Shunts, channels and lipoprotein endosomal traffic: a new model of cholesterol homeostasis in the hepatocyte

Abstract

The liver directs cholesterol metabolism in the organism. All the major fluxes of cholesterol within the body involve the liver: dietary cholesterol is directed to the liver; cholesterol from peripheral cells goes to the liver; the liver is a major site of cholesterol synthesis for the organism; cholesterol is secreted from the liver within the bile, within apoB lipoproteins and translocated to nascent HDL. The conventional model of cholesterol homeostasis posits that cholesterol from any source enters a common, rapidly exchangeable pool within the cell, which is in equilibrium with a regulatory pool. Increased influx of cholesterol leads rapidly to decreased synthesis of cholesterol. This model was developed based on in vitro studies in the fibroblast and validated only for LDL particles. The challenges the liver must meet in vivo to achieve cholesterol homeostasis are far more complex. Our model posits that the cholesterol derived from three different lipoproteins endosomes has three different fates: LDL-derived cholesterol is largely recycled within VLDL with most of the cholesterol shunted through the hepatocyte without entering the exchangeable pool of cholesterol; high density lipoprotein-derived CE is transcytosed into bile; and chylomicron remnant-derived cholesterol primarily enters the regulatory pool within the hepatocyte. These endosomal channels represent distinct physiological pathways and hepatic homeostasis represents the net result of the outcomes of these distinct channels. Our model takes into account the distinct physiological challenges the hepatocyte must meet, underlie the pathophysiology of many of the apoB dyslipoproteinemias and account for the sustained effectiveness of therapeutic agents such as statins.

Fig.1

Endosomal transport channels and regulation of lipoprotein-derived cholesterol in hepatocytes. In many models, it was thought that cholesterol from all sources would enter a common regulatory pool before subsequent trafficking and regulatory steps. We present evidence here that supports a model where there is independent uptake, trafficking and regulation of cholesterol taken up from LDL, chylomicron remnants (CR) and HDL. HDL-derived cholesterol is taken up by SR-BI or ecto-F1-ATPase/P2Y13 (right side), directed to the apical surface of the plasma membrane and released into the bile. CR-derived cholesterol (from the diet; middle section) is directed to the ER membrane to interact with SCAP (so-called “regulatory’ pool) to prevent release of SREBP2, thereby preventing upregulation of transcription of LDLR and HMGCR (among others). Excess cholesterol in the ER membrane can be esterified to CE by ACAT1 and stored within a cytosolic lipid droplet (LD). LDL-derived cholesterol is directed to a subdomain of the ER where the cholesterol is esterified by ACAT2. This CE is directed toward the lumen of the ER to interact with apoB-100 forming a precursor VLDL particle. Upon sufficient lipidation, the VLDL is secreted. Since the LDL-derived cholesterol bypasses SCAP (or other elements of the regulatory pool), we have termed this a shunt pathway. ABCA1/ABCG1 mediate cholesterol efflux to form HDL and reduce the cholesterol load in hepatocytes. Interestingly, cholesterol efflux and HDL biogenesis and then reuptake of HDL by SR-BI or P2Y13 may not represent a futile cycle if that cholesterol is redirected to bile acid secretion. All of these pathways represent channels with independent effectors mediating trafficking and regulation, with independent effects on intracellular cholesterol homeostasis.