Emerging roles of the intestine in control of cholesterol metabolism

Abstract

The liver is considered the major "control center" for maintenance of whole body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis, clears cholesterol-containing chylomicron remnants and low density lipoprotein particles from plasma and is the major contributor to high density lipoprotein (HDL; good cholesterol) formation. The liver has a central position in the classical definition of the reverse cholesterol transport pathway by taking up periphery-derived cholesterol from lipoprotein particles followed by conversion into bile acids or its direct secretion into bile for eventual removal via the feces. During the past couple of years, however, an additional important role of the intestine in maintenance of cholesterol homeostasis and regulation of plasma cholesterol levels has become apparent. Firstly, molecular mechanisms of cholesterol absorption have been elucidated and novel pharmacological compounds have been identified that interfere with the process and positively impact plasma cholesterol levels. Secondly, it is now evident that the intestine itself contributes to fecal neutral sterol loss as a cholesterol-secreting organ. Finally, very recent work has unequivocally demonstrated that the intestine contributes significantly to plasma HDL cholesterol levels. Thus, the intestine is a potential target for novel anti-atherosclerotic treatment strategies that, in addition to interference with cholesterol absorption, modulate direct cholesterol excretion and plasma HDL cholesterol levels.

Figure 1

Schematic overview of the major routes of cholesterol in enterocytes. Dietary and biliary cholesterol are taken up via the action of NPC1L1. In the ER, cholesterol is esterified and incorporated into chylomicrons, which are subsequently secreted into lymph. Non-esterified sterols can be re-secreted into the intestinal lumen via the action of ABCG5/G8 or secreted towards ApoA1 via the action of ABCA1. ABCA1, ABCG5, ABCG8: ATP-binding cassette transporter A1, G5, G8; ACAT2: Acyl-coenzyme A: Cholesterol acyl transferase 2; ApoAI, ApoB48, apolipoprotein AI, B48; C: Cholesterol; CE: Cholesterylester; ER: Endoplasmatisch reticulum; MTP: Microsomal triglyceride transfer protein; NPC1L1: Niemann Pick C 1 like 1 protein; SARA2: Sar1-ADP-ribosylation GTPase 2; TG: Triglycerides.

Figure 2

Schematic overview of the regulation of cholesterol transport in enterocytes. Plant sterols, ezetimibe PPARδ/β agonists and LXR agonists all reduce cholesterol absorption through different mechanisms. Plant sterols interfere with micellisation of cholesterol. Ezetimibe binds to NPC1L1 and thereby interferes with the cholesterol uptake. Agonists for PPARδ/β reduce expression of NPC1L1 and thereby the amount of NPC1L1 protein. Agonists for LXR increase the expression of ABCG5 and ABCG8 and thereby enhance the efflux of cholesterol towards the intestinal lumen. LXR: Liver X Receptor; PPARδ/β: Peroxisome proliferators-activated receptor δ/β.

Figure 3

Schematic overview of the involvement of the intestine in cholesterol homeostasis. The intestine is critically involved in the control of plasma cholesterol due to its role in intestinal cholesterol absorption (1), direct cholesterol excretion into the intestinal lumen (2), and HDL biogenesis (3). CM: Chylomicron; HDL: High density lipoprotein; LDL: Low density lipoprotein; VLDL: Very low density lipoprotein.