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Blackcurrant anthocyanins stimulated cholesterol transport via post-transcriptional induction of LDL receptor in Caco-2 cells

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Abstract

Purposes

We previously showed that polyphenol-rich blackcurrant extract (BCE) showed a hypocholesterolemic effect in mice fed a high fat diet. As direct cholesterol removal from the body via the intestine has been recently appreciated, we investigated the effect of BCE on the modulation of genes involved in intestinal cholesterol transport using Caco-2 cells as an in vitro model.

Methods

Caco-2 cells were treated with BCE to determine its effects on mRNA and protein expression of genes important for intestinal cholesterol transport, low-density lipoprotein (LDL) uptake, cellular cholesterol content, and cholesterol transport from basolateral to apical membrane of Caco-2 cell monolayers. Cells were also treated with anthocyanin-rich or -poor fraction of BCE to determine the role of anthocyanin on BCE effects.

Results

BCE significantly increased protein levels of LDL receptor (LDLR) without altering its mRNA, which consequently increased LDL uptake into Caco-2 cells. This post-transcriptional induction of LDLR by BCE was markedly attenuated in the presence of rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1). In addition, BCE altered genes involved in cholesterol transport in the enterocytes, including apical and basolateral cholesterol transporters, in such a way that could enhance cholesterol flux from the basolateral to apical side of the enterocytes. Indeed, BCE significantly increased the flux of LDL-derived cholesterol from the basolateral to the apical chamber of Caco-2 monolayer. LDLR protein levels were markedly increased by anthocyanin-rich fraction, but not by anthocyanin-free fraction.

Conclusion

mTORC1-dependent post-transcriptional induction of LDLR by BCE anthocyanins drove the transport of LDL-derived cholesterol to the apical side of the enterocytes. This may represent a potential mechanism for the hypocholesterolemic effect of BCE.

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Abbreviations

ABC:

ATP-binding cassette transporter

ACAT2:

Acetyl-CoA acetyltransferase 2

ACOX-1:

Acyl-CoA oxidase 1

BAF:

Anthocyanin-free fraction of BCE

BAR:

Anthocyanin-rich fraction of BCE

BCE:

Black currant extract

CAF:

Anthocyanin-free fraction of CBE

CAR:

Anthocyanin-rich fraction of CBE

CBE:

Black chokeberry extract

CVD:

Cardiovascular disease

FAS:

Fatty acid synthase

HDL:

High-density lipoprotein

HMGR:

3-Hydroxy-3-methyl-glutaryl coenzyme A reductase

LDLR:

LDL receptor

mTORC1:

Mechanistic target of rapamycin complex 1

NPC1L1:

Niemann-Pick C1 like 1

MTTP:

Microsomal triglyceride transfer protein

SCD-1:

Stearoyl CoA desaturase-1

SR-BI:

Scavenger receptor class B, type I

SREBP:

Sterol regulatory element-binding protein

PCSK9:

Proprotein convertase subtilisin/kexin type 9

TICE:

Trans-intestinal cholesterol excretion

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Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2012R1A6A3A03039945) to B. Kim and by USDA AFRI 2016-67017-24463, USDA Hatch Grant (CONS00972), and USDA Multi-State Hatch Grant (CONS00916) to J. Lee.

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Authors and Affiliations

  1. Department of Nutritional Sciences, University of Connecticut, Storrs, CT, 06269-4017, USA

    Bohkyung Kim, Minkyung Bae, Young-Ki Park & Ji-Young Lee

  2. Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, 02881, USA

    Hang Ma, Tao Yuan & Navindra P. Seeram

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  1. Bohkyung Kim
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Kim, B., Bae, M., Park, YK. et al. Blackcurrant anthocyanins stimulated cholesterol transport via post-transcriptional induction of LDL receptor in Caco-2 cells. Eur J Nutr 57, 405–415 (2018). https://doi.org/10.1007/s00394-017-1506-z

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