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Review
. 2015 Jul;36(7):440-51.
doi: 10.1016/j.tips.2015.04.002. Epub 2015 Apr 27.

A new model of reverse cholesterol transport: enTICEing strategies to stimulate intestinal cholesterol excretion

Ryan E Temel  1 , J Mark Brown  2
Affiliations
Review

A new model of reverse cholesterol transport: enTICEing strategies to stimulate intestinal cholesterol excretion

Ryan E Temel et al. Trends Pharmacol Sci. 2015 Jul.

Abstract

Cardiovascular disease (CVD) remains the largest cause of mortality in most developed countries. Although recent failed clinical trials and Mendelian randomization studies have called into question the high-density lipoprotein (HDL) hypothesis, it remains well accepted that stimulating the process of reverse cholesterol transport (RCT) can prevent or even regress atherosclerosis. The prevailing model for RCT is that cholesterol from the artery wall must be delivered to the liver where it is secreted into bile before leaving the body through fecal excretion. However, many studies have demonstrated that RCT can proceed through a non-biliary pathway known as transintestinal cholesterol excretion (TICE). The goal of this review is to discuss the current state of knowledge of the TICE pathway, with emphasis on points of therapeutic intervention.

Keywords: bile; cholesterol; lipoprotein; reverse cholesterol transport; transintestinal cholesterol excretion.

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Conflict of interest statement

The authors report that they have no conflicts of interest.

Figures

Figure 1
Figure 1. Model for Integrated Biliary and Non-Biliary Reverse Cholesterol Transport
Nascent HDL particles circulate to remove cholesterol from peripheral tissues and macrophage foam cells in the artery wall plaque. Once matured with both free and esterified cholesterol cargo, HDL is cleared by the liver primarily via SR-BI-dependent selective uptake. Importantly, in CETP-containing species, a large portion of HDL’s cholesteryl ester cargo can be transferred to apoB-containing lipoproteins by CETP, which are taken up by the liver by hepatic low density lipoprotein receptors (LDLR) contributing to overall RCT flux. As shown by black arrows, all steps up to this point represent well understood pathways in RCT, and this shared centripetal flux collectively delivers cholesterol to the liver where this cargo then can branch into either biliary or less understood non-biliary pathways. As denoted with blue arrows, a large portion of the HDL-derived cholesterol pool can be secreted into bile via the actions of proteins such as ATP-binding cassette transporters G5 and G8 and other minor mechanisms. Once cholesterol is secreted into bile a large portion of this pool is physically delivered to the lumen of the small intestine via the common bile duct, where it can ultimately provide substrate for fecal cholesterol loss. Alternatively, highlighted by red arrows, the liver can initiate the non-biliary TICE pathway to eliminate excess cholesterol. Current evidence suggests that the non-biliary branch of RCT can be initiated by either re-uptake of biliary cholesterol via the cannalicular sterol transporter NPC1L1 among other mechanisms. Following NPC1L1-dependent recovery of biliary cholesterol, the excess free cholesterol is moved to the ER where it is repackaged onto nascent apoB-containing lipoproteins, which are ultimately secreted from the liver into the bloodstream. The liver-derived apoB-containing lipoproteins are then recognized by the proximal small intestine through lipoprotein receptors such as LDLr, and likely other mechanisms. Once cleared by the proximal small intestine, TICE-derived cholesterol is directionally trafficked across the enterocyte in a basolateral to apical fashion, and this cholesterol can be effluxed across the apical membrane via the actions of ATP binding cassette transporters ABCG5/ABCG8, ABCB1a/b, and likely other mechanisms. Collectively this TICE flux through the intestine, coupled with biliary cholesterol secretion, and dietary cholesterol make up the sum total of cholesterol available for excretion into the feces. New evidence suggests that the hepatic enzyme flavin containing monooxygenase 3 add another level of control, functioning to balance RCT flux by enhancing the biliary pathway and suppressing the TICE pathway. Abbreviations used: ABCB1a/b = ATP-binding cassette transporter 1a/b; ABCG5/G8 = ATP-binding cassette transporters G5 and G8; ACAT2 = acyl-CoA:cholesterol acyltransferase 2; apoB = apolipoprotein B; CE = cholesteryl ester; ER = endoplasmic reticulum; FC = free cholesterol; FMO3 = flavin containing monooxygenase 3; HDL = high density lipoprotein; LDL = low density lipoprotein; LDLR = low density lipoprotein receptor; MTP = microsomal triglyceride transfer protein; NPC1L1 = Niemann-Pick C1-like 1; PCSK9 = proprotein convertase subtilisin/kexin type 9; SR-BI = scavenger receptor class B class I; TICE = transintestinal cholesterol excretion; ? = unknown proteins.
Figure 2
Figure 2. Model for Cholesterol Flux Across the Intestinal Enterocyte
The intestinal enterocyte is a gatekeeper of cholesterol balance with two opposing pathways delivering cholesterol from opposite sides of this polarized cell. First, the cholesterol absorption pathway is initiated by NPC1L1-dependent delivery of dietary and biliary cholesterol to the ER, where it is packaged into nascent chylomicron particles for delivery into the lymphatics. Directly opposing the absorptive pathway, TICE flux is driven by the delivery of liver-derived apoB-containing lipoproteins that are taken up by the LDL receptor and likely other receptors. Once internalized these lipoproteins are trafficked through endosomal and lysosomal compartments, and ultimately effluxed from the apical membrane through ABCG5/ABCG8, ABCB1a/b, and likely other transporter. A portion of this newly effluxed cholesterol can be excreted into the feces. Collectively, these two opposing influx pathways (absorption and TICE) along with endogenous cholesterol synthesis comprise the total enterocyte cholesterol pool. Abbreviations used: ABCB1a/b = ATP-binding cassette transporter 1a/b; ABCG5/G8 = ATP-binding cassette transporters G5 and G8; apoB = apolipoprotein B; ER = endoplasmic reticulum; LDLR = low density lipoprotein receptor; NPC1L1 = Niemann-Pick C1-like 1; TICE = transintestinal cholesterol excretion; ? = unknown receptor mediating the uptake of TICE lipoproteins.
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References

    1. Go AS, et al. Executive summary: heart disease and stroke statistics – 2013 update: a report from the American Heart Association. Circulation. 2013;127:143–152. - PubMed
    1. Rader DJ, Tall AR. The not-so-simply HDL story: Is it time to revise the HDL cholesterol hypothesis? Nat Med. 2012;18:1344–1346. - PubMed
    1. Boden WE, et al. AIM-HIGH investigators. (2011) Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 365:2255–2267. - PubMed
    1. Schwartz GG, et al. Effect of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–2099. - PubMed
    1. Voight BF, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012;380:572–580. - PMC - PubMed

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