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Increased hepatic ABCA1 transporter is associated with hypercholesterolemia in a cholestatic rat model and primary biliary cholangitis patients

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Abstract

Hepatic ATP-binding cassette A1 (ABCA1) transporter is the modulator of intrahepatic cholesterol levels via the efflux of cholesterol into plasma. This study aimed to determine the expression of hepatic ABCA1 levels in a cholestatic rat model and patients with primary biliary cholangitis (PBC). A cholesterol efflux study was conducted with Abca1 knock down using siRNA in WIF9 cells. Cholesterol levels in the ABCA1 siRNA cells in the medium were significantly decreased compared with those in controls (P < 0.05). Hepatic ABCA1 mRNA levels were significantly higher in BDL rats than in control rats (P < 0.05). Furthermore, the protein expression level of hepatic ABCA1 was also significantly increased by 200% in BDL rats (P < 0.05). In PBC patients, expression of hepatic ABCA1 mRNA was 2.2-fold higher than that in controls (P < 0.05). The level of hepatic liver X receptor (LXR)β mRNA was correlated with ABCA1 mRNA levels in PBC patients. The expression of hepatic ABCA1 transporter was upregulated in both the cholestatic rat model and PBC patients. Upregulated hepatic ABCA1 may lead to efflux of cholesterol into plasma, thus explaining the mechanism of cholestasis leading to hypercholesterolemia.

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Abbreviations

ABCA1:

ATP-binding cassette transporter A1

HDL:

High-density lipoprotein

GFP:

Green fluorescent protein

BDL:

Bile duct ligation

siRNA:

Short interfering RNA

FTF:

Fetoprotein transcriptional factor

MRP3:

Multidrug resistance-associated protein 3

FRX:

Farnesoid X receptor

CYP7A1:

Cholesterol 7-hydroxylase

LXRα:

Liver X receptor α

EMSA:

Electrophoretic mobility shift assay

RXR:

Retinoid X receptor

DR4:

Direct repeat 4

SWH:

Southwestern histochemistry

PBC:

Primary biliary cholangitis

RT:

Reverse transcriptase

PCR:

Polymerase chain reaction

SHP:

Small heterodimer partner

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Acknowledgements

We thank Dr. Yoshio Misumi, Ms. Akiko Ono, Ms. Motoko Kawashima, Ms. Kazuko Kanegae, and Ms. Eri Yamauchi for their excellent technical assistance. This work was supported by a Grant from the Clinical Research Foundation and supported partially by the Research Program of Intractable Disease provided by the Ministry of Health, Labor, and Welfare of Japan. The WIF-B9 cells were kindly provided by Professor Ann L. Hubbard (Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA).

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Authors and Affiliations

  1. Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, 7-45-1 Nanakuma, Jonan Ward, Fukuoka, 814-0180, Japan

    Yasuaki Takeyama, Yuko Uehara, Akira Anan, Daisuke Morihara, Keiji Yokoyama, Kazuhide Takata, Takashi Tanaka, Makoto Irie, Kaoru Iwata, Satoshi Shakado, Tetsuro Sohda & Shotaro Sakisaka

  2. Internal Medicine, Meotoiwa Hospital, Fukuoka, Japan

    Kaoru Iwata

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  1. Yasuaki Takeyama
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Correspondence to Yasuaki Takeyama.

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The Clinical Research Foundation, the Research Program of Intractable Disease provided by the Ministry of Health, Labor, and Welfare of Japan.

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Takeyama, Y., Uehara, Y., Anan, A. et al. Increased hepatic ABCA1 transporter is associated with hypercholesterolemia in a cholestatic rat model and primary biliary cholangitis patients. Med Mol Morphol 50, 227–237 (2017). https://doi.org/10.1007/s00795-017-0166-7

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  • DOI: https://doi.org/10.1007/s00795-017-0166-7

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