Physicians' Academy for Cardiovascular Education

TICE pathway actively excretes cholesterol and can be modified by PCSK9 and statins

Literature - Le May C, Berger JM, Lespine A et al. - Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1484-1493.


Transintestinal Cholesterol Excretion Is an Active Metabolic Process Modulated by PCSK9 and Statin Involving ABCB1.

 
Le May C, Berger JM, Lespine A et al.
Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1484-1493.
 

Background

The hepatobiliary pathway has long been considered as the major cholesterol elimination route. A non-biliary route contributing to fecal sterol loss has now also been identified in dogs, rats and later humans with impaired biliary excretion [1]. Transintestinal cholesterol excretion (TICE) is now considered a significant alternative route to the hepatobiliary pathway [2]. No evidence has been published thus far for TICE in humans. In mice TICE may account for 33% of total fecal sterol loss [3]. A potential anti-atherogenic role for TICE was suggested by observations in mice that TICE is essential to macrophage reverse cholesterol transport [4].
The hepatic LDL-receptor (LDLR) [5] and the Scavenger receptor B1 [6] are important for classical hepatobiliary cholesterol clearance. LDLR is also expressed in the intestine. LDLR density depends on cholesterol levels, transcription upregulation by statins [5] and increased LDLR degradation by PCSK9 [7]. ATP-binding cassette transporter B1 contributes to cholesterol distribution [8].
Despite these insights, much remains unknown about the precise nature and mechanisms of the TICE pathway. Using transgenic mice (PCSK9+/- and LDLR-/-) and human samples, this study aimed to answer some of the remaining questions.
 

Main results

  • An in vivo method was developed using mouse duodenal explants, which showed that LDL-transport is an active metabolic pathway.
  • Both HDL and LDL can provide cholesterol for TICE in vitro and in vivo in mice.
  • TICE was also detected in human jejunal explants.
  • In PCSK9-deficient mice, TICE via LDL was increased.
  • Degradation of LDLR by recombinant circulating PCSK9 results in decreased TICE.
  • TICE was activated by the cholesterol synthesis inhibitor Lovastatin.
  • The above results suggest that LDLR plays an important role in TICE, and that TICE might be reduced in LDLR-/- mice. Surprisingly, LDLR-/- mice showed slightly higher (non-significantly but reproducibly) TICE than wildtype mice, seemingly due to increased LDL uptake in the proximal intestine.
  • Mice deficient for the multidrug transporter ABCB1a and -1b showed less fecal cholesterol excretion. Pharmacological inhibition of these transporters also provided evidence that ABCB1a/b contribute to TICE.
 

Conclusion

This study contributes to our understanding of plasma cholesterol excretion by the small intestine. It provides the first direct evidence that human intestinal explants can excrete LDL-C and HDL-C. LDL-TICE can be modulated positively by statins and negatively by PCSK9. TICE and cholesterolemia seem inversely related, implying that TICE is an active process rather than a concentration-dependent process.
 

Editorial comment [9]

The work by Le May et al. represents an important advancement of our understanding of TICE.
Their data on HDL are unexpected and in contrast with earlier findings. Additional studies will need to resolve this issue.
The data suggest a potential involvement of LDLR on the basolateral side, as TICE could be repressed by PCSK9 and activated by a statin. This calls for translational medicine, using the newly emerging PCSK9 inhibiting treatments.
The discovered link between TICE and the LDL pathway is particularly promising. Given the current challenges in the HDL field, a new way to preferentially excrete the proatherogenic LDL-C from the body can have a major impact on the fight against atherosclerotic cardiovascular disease.
 



References

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4. Temel RE, Sawyer JK, Yu L, et al. Biliary sterol secretion is not required for macrophage reverse cholesterol transport. Cell Metab. 2010;12:96–102.
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6. Acton S, Rigotti A, Landschulz KT, et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science. 1996;271:518–520.
7. Rashid S, Curtis DE, Garuti R, et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci USA. 2005;102:5374–5379.
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9. Tietge UJF, Groen AK. Role the DICE?: Advancing the concept of transinstinal cholesterol excretion. Arterioscler Thromb Vasc Biol. 2013;33:1452-1453
 

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