Skip to main content

Advertisement

SpringerLink
Log in

The TICE Pathway: Mechanisms and Potential Clinical Applications

  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Transintestinal cholesterol excretion (TICE) is a non-biliary pathway that excretes excess cholesterol from the body through feces. This article focuses on the research progress of the TICE pathway in the last few years, including the discovery process of the TICE pathway, its molecular mechanism, and potential clinical applications.

Recent Findings

Cholesterol homeostasis is vital for cardiovascular diseases, stroke, and neurodegenerative diseases. Beyond the cholesterol excretion via hepatobiliary pathway, TICE contributes significantly to reverse cholesterol transport ex vivo and in vivo. Nuclear receptors are ligand-activated transcription factors that regulate cholesterol metabolism. The farnesoid X receptor (FXR) and liver X receptor (LXR) activated, respectively, by oxysterols and bile acids promote intestinal cholesterol secretion through ABCG5/G8. Nutrient regulators and intestinal flora also modulate cholesterol secretion through the TICE pathway. TICE allows direct elimination of plasma cholesterol, which may provide an attractive therapeutic targets.

Summary

TICE pathway may provide a potential target to stimulate cholesterol elimination and reduce the risk of cardiovascular diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Hu J, et al. Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutr Metab (Lond). 2010;7:47.

    Article  PubMed  Google Scholar 

  2. Tabas I, García-Cardeña G, Owens GK. Recent insights into the cellular biology of atherosclerosis. J Cell Biol. 2015;209(1):13–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Glomset JA, Norum KR. The metabolic role of lecithin: cholesterol acyltransferase: perspectives form pathology. Adv Lipid Res. 1973;11:1–65.

    Article  CAS  PubMed  Google Scholar 

  4. Garçon D, et al. Transintestinal cholesterol excretion in health and disease. Curr Atheroscler Rep. 2022;24(3):153–60.

    Article  PubMed  Google Scholar 

  5. Stellaard, F. From dietary cholesterol to blood cholesterol, physiological lipid fluxes, and cholesterol homeostasis. Nutrients. 2022; 14(8).

  6. de Boer JF, et al. Intestinal Farnesoid X receptor controls transintestinal cholesterol excretion in mice. Gastroenterology. 2017;152(5):1126-1138.e6.

    Article  PubMed  Google Scholar 

  7. Tanaka Y, Kamisako T. Regulation of the expression of cholesterol transporters by lipid-lowering drugs ezetimibe and pemafibrate in rat liver and intestine. Biochim Biophys Acta Mol Basis Dis. 2021;1867(11):166215.

    Article  CAS  PubMed  Google Scholar 

  8. •• Luo, J., H. Yang, B.L. Song. Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol, 2020. 21(4): 225–245. The study identified the key factors that govern the four pathways of cholesterol biosynthesis, uptake, export and esterification, and the main mechanisms by which they respond to different sterol levels.

  9. Ouimet M, Barrett TJ, Fisher EA. HDL and reverse cholesterol transport. Circ Res. 2019;124(10):1505–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Goedeke L, Fernández-Hernando C. Regulation of cholesterol homeostasis. Cell Mol Life Sci. 2012;69(6):915–30.

    Article  CAS  PubMed  Google Scholar 

  11. Brown MS, Goldstein JL. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci U S A. 1999;96(20):11041–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell. 2006;124(1):35–46.

    Article  CAS  PubMed  Google Scholar 

  13. Sun LP, et al. Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro. J Biol Chem. 2005;280(28):26483–90.

    Article  CAS  PubMed  Google Scholar 

  14. Sever N, et al. Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Mol Cell. 2003;11(1):25–33.

    Article  CAS  PubMed  Google Scholar 

  15. Goldstein JL, Rawson RB, Brown MS. Mutant mammalian cells as tools to delineate the sterol regulatory element-binding protein pathway for feedback regulation of lipid synthesis. Arch Biochem Biophys. 2002;397(2):139–48.

    Article  CAS  PubMed  Google Scholar 

  16. Altmann SW, et al. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science. 2004;303(5661):1201–4.

    Article  CAS  PubMed  Google Scholar 

  17. van Heek M, et al. Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function. Br J Pharmacol. 2001;134(2):409–17.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Garcia-Calvo M, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci U S A. 2005;102(23):8132–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Altmann SW, et al. The identification of intestinal scavenger receptor class B, type I (SR-BI) by expression cloning and its role in cholesterol absorption. Biochim Biophys Acta. 2002;1580(1):77–93.

    Article  CAS  PubMed  Google Scholar 

  20. Li PS, et al. The clathrin adaptor Numb regulates intestinal cholesterol absorption through dynamic interaction with NPC1L1. Nat Med. 2014;20(1):80–6.

    Article  PubMed  Google Scholar 

  21. Johnson TA, Pfeffer SR. Ezetimibe-sensitive cholesterol uptake by NPC1L1 protein does not require endocytosis. Mol Biol Cell. 2016;27(11):1845–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jia L, Betters JL, Yu L. Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annu Rev Physiol. 2011;73:239–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Anderson RA, et al. Identification of a form of acyl-CoA:cholesterol acyltransferase specific to liver and intestine in nonhuman primates. J Biol Chem. 1998;273(41):26747–54.

    Article  CAS  PubMed  Google Scholar 

  24. Ingram MF, Shelness GS. Folding of the amino-terminal domain of apolipoprotein B initiates microsomal triglyceride transfer protein-dependent lipid transfer to nascent very low density lipoprotein. J Biol Chem. 1997;272(15):10279–86.

    Article  CAS  PubMed  Google Scholar 

  25. Berge KE, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 2000;290(5497):1771–5.

    Article  CAS  PubMed  Google Scholar 

  26. Lee MH, et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet. 2001;27(1):79–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yu L, et al. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci U S A. 2002;99(25):16237–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yu L, et al. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest. 2002;110(5):671–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Temel RE, et al. Intestinal cholesterol absorption is substantially reduced in mice deficient in both ABCA1 and ACAT2. J Lipid Res. 2005;46(11):2423–31.

    Article  CAS  PubMed  Google Scholar 

  30. Brunham LR, et al. Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J Clin Invest. 2006;116(4):1052–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tang W, et al. Niemann-Pick C1-like 1 is required for an LXR agonist to raise plasma HDL cholesterol in mice. Arterioscler Thromb Vasc Biol. 2008;28(3):448–54.

    Article  CAS  PubMed  Google Scholar 

  32. Doonan LM, Fisher EA, Brodsky JL. Can modulators of apolipoproteinB biogenesis serve as an alternate target for cholesterol-lowering drugs? Biochim Biophys Acta Mol Cell Biol Lipids. 2018;1863(7):762–71.

    Article  CAS  PubMed  Google Scholar 

  33. Yu L, et al. Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion. J Biol Chem. 2005;280(10):8742–7.

    Article  CAS  PubMed  Google Scholar 

  34. Cheng SH, Stanley MM. Secretion of cholesterol by intestinal mucosa in patients with complete common bile duct obstruction. Proc Soc Exp Biol Med. 1959;101(2):223–5.

    Article  CAS  PubMed  Google Scholar 

  35. van der Velde AE, et al. Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice. Gastroenterology. 2007;133(3):967–75.

    Article  PubMed  Google Scholar 

  36. Smit JJ, et al. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell. 1993;75(3):451–62.

    Article  CAS  PubMed  Google Scholar 

  37. Brown JM, et al. Targeted depletion of hepatic ACAT2-driven cholesterol esterification reveals a non-biliary route for fecal neutral sterol loss. J Biol Chem. 2008;283(16):10522–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Simmonds WJ, Hofmann AF, Theodor E. Absorption of cholesterol from a micellar solution: intestinal perfusion studies in man. J Clin Invest. 1967;46(5):874–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Le May C, et al. Transintestinal cholesterol excretion is an active metabolic process modulated by PCSK9 and statin involving ABCB1. Arterioscler Thromb Vasc Biol. 2013;33(7):1484–93.

    Article  PubMed  Google Scholar 

  40. Jakulj L, et al. Transintestinal cholesterol transport is active in mice and humans and controls ezetimibe-induced fecal neutral sterol excretion. Cell Metab. 2016;24(6):783–94.

    Article  CAS  PubMed  Google Scholar 

  41. Moreau F, et al. In vivo evidence for transintestinal cholesterol efflux in patients with complete common bile duct obstruction. J Clin Lipidol. 2019;13(1):213-217.e1.

    Article  PubMed  Google Scholar 

  42. Hirata T, et al. Molecular mechanisms of subcellular localization of ABCG5 and ABCG8. Biosci Biotechnol Biochem. 2009;73(3):619–26.

    Article  CAS  PubMed  Google Scholar 

  43. Lu K, et al. Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. Am J Hum Genet. 2001;69(2):278–90.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Sabeva NS, Rouse EJ, Graf GA. Defects in the leptin axis reduce abundance of the ABCG5-ABCG8 sterol transporter in liver. J Biol Chem. 2007;282(31):22397–405.

    Article  CAS  PubMed  Google Scholar 

  45. Langheim S, et al. ABCG5 and ABCG8 require MDR2 for secretion of cholesterol into bile. J Lipid Res. 2005;46(8):1732–8.

    Article  CAS  PubMed  Google Scholar 

  46. Wang J, et al. Relative roles of ABCG5/ABCG8 in liver and intestine. J Lipid Res. 2015;56(2):319–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Brown JM, Yu L. Opposing gatekeepers of apical sterol transport: Niemann-Pick C1-like 1 (NPC1L1) and ATP-binding cassette transporters G5 and G8 (ABCG5/ABCG8). Immunol Endocr Metab Agents Med Chem. 2009;9(1):18–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jakulj L, et al. Ezetimibe stimulates faecal neutral sterol excretion depending on abcg8 function in mice. FEBS Lett. 2010;584(16):3625–8.

    Article  CAS  PubMed  Google Scholar 

  49. van der Velde AE, et al. Regulation of direct transintestinal cholesterol excretion in mice. Am J Physiol Gastrointest Liver Physiol. 2008;295(1):G203-g208.

    Article  PubMed  Google Scholar 

  50. Inagaki T, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005;2(4):217–25.

    Article  CAS  PubMed  Google Scholar 

  51. •• Blankestijn, M., et al., Induction of fecal cholesterol excretion is not effective for the treatment of hyperbilirubinemia in Gunn rats. Pediatr Res. 2021; 89(3): 510–517. Findings from this study suggest that OCA enhanced TICE by activating FXR.

  52. Janowski BA, et al. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996;383(6602):728–31.

    Article  CAS  PubMed  Google Scholar 

  53. Plōsch T, et al. Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1. J Biol Chem. 2002;277(37):33870–7.

    Article  PubMed  Google Scholar 

  54. Repa JJ, et al. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science. 2000;289(5484):1524–9.

    Article  CAS  PubMed  Google Scholar 

  55. Kruit JK, et al. Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice. Gastroenterology. 2005;128(1):147–56.

    Article  CAS  PubMed  Google Scholar 

  56. van der Veen JN, et al. Activation of the liver X receptor stimulates trans-intestinal excretion of plasma cholesterol. J Biol Chem. 2009;284(29):19211–9.

    Article  PubMed  PubMed Central  Google Scholar 

  57. • Lifsey HC et al. Stigmasterol stimulates transintestinal cholesterol excretion independent of liver X receptor activation in the small intestine. J NutrBiochem, 2020; 76: 108263.  This study shows that LXR agonist T0901317 stimulates the TICE pathway by increasing the expression of ABCG5 and ABCG8 in the liver and duodenum.

  58. Grefhorst A, et al. Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J Biol Chem. 2002;277(37):34182–90.

    Article  CAS  PubMed  Google Scholar 

  59. van der Veen JN, et al. Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1. J Lipid Res. 2005;46(3):526–34.

    Article  PubMed  Google Scholar 

  60. Oliver WR Jr, et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A. 2001;98(9):5306–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sprecher DL, et al. Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist. Arterioscler Thromb Vasc Biol. 2007;27(2):359–65.

    Article  CAS  PubMed  Google Scholar 

  62. Zhang DW, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 2007;282(25):18602–12.

    Article  CAS  PubMed  Google Scholar 

  63. Sachdev V, et al. Novel role of a triglyceride-synthesizing enzyme: DGAT1 at the crossroad between triglyceride and cholesterol metabolism. Biochim Biophys Acta. 2016;1861(9 Pt A):1132–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Marshall SM, et al. Acute sterol o-acyltransferase 2 (SOAT2) knockdown rapidly mobilizes hepatic cholesterol for fecal excretion. PLoS One. 2014;9(6):e98953.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Sokolović M, et al. Unexpected effects of fasting on murine lipid homeostasis–transcriptomic and lipid profiling. J Hepatol. 2010;52(5):737–44.

    Article  PubMed  Google Scholar 

  66. Calpe-Berdiel L, Escolà-Gil JC, Blanco-Vaca F. New insights into the molecular actions of plant sterols and stanols in cholesterol metabolism. Atherosclerosis. 2009;203(1):18–31.

    Article  CAS  PubMed  Google Scholar 

  67. Brufau G, et al. A reappraisal of the mechanism by which plant sterols promote neutral sterol loss in mice. PLoS One. 2011;6(6):e21576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Koeth RA, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wang Z, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sehayek E, Hazen SL. Cholesterol absorption from the intestine is a major determinant of reverse cholesterol transport from peripheral tissue macrophages. Arterioscler Thromb Vasc Biol. 2008;28(7):1296–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Warrier M, et al. The TMAO-Generating enzyme flavin monooxygenase 3 is a central regulator of cholesterol balance. Cell Rep. 2015;10(3):326–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Vrins CL, et al. Peroxisome proliferator-activated receptor delta activation leads to increased transintestinal cholesterol efflux. J Lipid Res. 2009;50(10):2046–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chandak PG, et al. Lack of acyl-CoA:diacylglycerol acyltransferase 1 reduces intestinal cholesterol absorption and attenuates atherosclerosis in apolipoprotein E knockout mice. Biochim Biophys Acta. 2011;1811(12):1011–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the Natural Science Foundation of Henan Province (grant number 182300410316, Y.Z.), the Key Program for Science and Technology of Henan Province (grant number 202102310808, W.L.), the Key Program for Science and Technology of Henan Province (grant number 222102310578, P.L.), and the Co-constructed Program for Medical Science and Technology of Henan Province (grant numbers LHGJ20191297, P.L.).

Author information

Authors and Affiliations

  1. Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Henan, China

    Huimin Xu, Yiyang Xin, Jiaxin Wang, Zixin Liu, Yutong Cao & Yun Zhou

  2. People’s Hospital of Hebi, Henan University, Henan, China

    Weiguo Li & Peng Liu

  3. State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China

    Yandong Wang

Authors
  1. Huimin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yiyang Xin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiaxin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zixin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yutong Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Weiguo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yun Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yandong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Peng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Huimin Xu drafted the article. Yiyang Xin conducted the figures. Jiaxin Wang and Zixin Liu reviewed the article. Yutong Cao and Weiguo Li revised the article. Peng Liu, Yandong Wang, and Yun Zhou guided the writing.

Corresponding authors

Correspondence to Yun Zhou, Yandong Wang or Peng Liu.

Ethics declarations

Consent to Participate

The authors consented to participate.

Consent to Publish

The authors agreed to publish this paper.

Conflict of Interest

The authors declare no competing interests.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, H., Xin, Y., Wang, J. et al. The TICE Pathway: Mechanisms and Potential Clinical Applications. Curr Atheroscler Rep 25, 653–662 (2023). https://doi.org/10.1007/s11883-023-01147-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11883-023-01147-6

Keywords

Search

Navigation