Molecular Pathways Underlying Cholesterol Homeostasis

Abstract

Cholesterol is an essential molecule that exerts pleiotropic actions. Although its presence is vital to the cell, its excess can be harmful and, therefore, sustaining cholesterol homeostasis is crucial to maintaining proper cellular functioning. It is well documented that high plasma cholesterol concentration increases the risk of atherosclerotic heart disease. In the last decades, several studies have investigated the association of plasma cholesterol concentrations and the risk of cardiovascular diseases as well as the signaling pathways involved in cholesterol homeostasis. Here, we present an overview of several mechanisms involved in intestinal cholesterol absorption, the regulation of cholesterol synthesis and uptake. We also discuss the importance of reverse cholesterol transport and transintestinal cholesterol transport to maintain cholesterol homeostasis and prevent atherosclerosis development. Additionally, we discuss the influence of dietary cholesterol on plasma cholesterol concentration and the new recommendations for cholesterol intake in a context of a healthy dietary pattern.

Keywords: cardiovascular disease; cholesterol; cholesterol homeostasis; dietary cholesterol; molecular pathways.

Figure 1

Mechanisms involved in cholesterol absorption. Free cholesterol (FC) transported in the micelles enter the enterocyte through NPC1L1 and is esterified by ACAT2 in the endoplasmic reticulum (ER). Free cholesterol returns to the intestinal lumen via ABCG5/G8 transporters. Cholesteryl ester, triglycerides, and apolipoprotein B-48 (apo B-48), are further processed in the Golgi complex (GC) to form chylomicrons (CM), which are then transferred to the lymphatic system. NPC1L1 and ABCG5/8 expression is controlled by the cholesterol sensors LXRα and LXRβ. Both isoforms inhibit NPC1L1 and activate ABCG5/G8 inducing cholesterol excretion back to the lumen. LXR can also induce ABCA1-mediated cholesterol efflux to prevent cholesterol accumulation in the enterocytes.

Figure 2

Regulation of cholesterol biosynthesis. The master regulator of cholesterol synthesis and uptake, SREBP-2, is attached to the ER membrane through the interaction with SCAP and Insig-1. In a state of a reduced levels of cholesterol, Insig-1 undergoes proteasomal degradation and the complex SCAP-SREBP is sorted into COPII-coated vesicles, in a process mediated by a small GTPase, Sar1 and the coat proteins Sec23/Sec24 and Sec13/Sec31. COPII coat vesicles escort the SCAP-SREBP complex from ER to Golgi, where SREBP is cleaved by two resident proteases, site-1 (S1P) and site-2 (S2P), releasing its NH2-active domain. In the nucleus, SREBP binds to the SRE inducing the transcription of genes involved in cholesterol synthesis such as HMGCR, HMGS, and MVK, as well as LDLR which is responsible for cholesterol uptake, in an attempt to restore the intracellular cholesterol concentrations. ER: endoplasmic reticulum, SREBP-2: sterol regulatory element-binding protein-2; SCAP: SREBP cleavage-activating protein; Insig-1: Insulin-induced gene protein-1.

Figure 3

The regulatory pathways of reverse cholesterol transport: oxLDL contributes to atherogenesis by delivering cholesterol and oxysterol to macrophages in a process mediated by scavenger receptors (CD36, SR-A, SR-BI and LOX-1) present on the surface of these cells. Oxysterols are strong ligands of LXR, which heterodimerizes with RXR, and therefore induces ABCA1 and ABCG1 expression. ABCA1 promotes cholesterol efflux to apoA-I, while ABCG1 removes cholesterol from cells by interacting with HDL. The FC present in the discoidal lipid-poor apoA-I is esterified to an acyl chain through LCAT. The cholesterol acceptors apoA-I and HDL drive cholesterol from the periphery to the liver for bile secretion. HDL delivers cholesterol to the liver after partial hydrolysis of its triglycerides and phospholipids content by hepatic lipase, resulting in a smaller particle that is taken up by SR-BI. Cholesterol can also be delivered to the liver through B/E receptor in a process mediated by CETP, which transfers cholesterol from HDL to the apo B rich particles. In the liver, cholesterol is converted into bile acids and secreted in to the bile. Cholesterol from plasma lipoproteins can also be taken up by enterocytes at the basolateral membrane and subsequently excreted into the lumen by ABCG5/G8 in an alternative, non-biliary route known as TICE. FC: free cholesterol; CE: cholesterol ester; TG: triglycerides; CETP: cholesteryl ester transfer protein; LCAT: lecithin: cholesterol acyltransferase; TICE: trans-intestinal cholesterol excretion.