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Tenofovir–disoproxil–fumarate modulates lipid metabolism via hepatic CD36/PPAR-alpha activation in hepatitis B virus infection

  • Original Article—Liver, Pancreas, and Biliary Tract
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Abstract

Background

Entecavir and tenofovir–disoproxil–fumarate are first-line nucleos(t)ide analogs (NA) for treatment of hepatitis B virus (HBV) infections; however, their long-term administration can impact extrahepatic organs. Herein, we sought to examine the effect of NA on lipid metabolism while also characterizing the associated mechanism.

Methods

A retrospective study was performed on HBV patients administered entecavir or tenofovir–disoproxil–fumarate. Patient clinical information, as well as their preserved serum samples obtained at baseline and 6–12 months after treatment initiation, were analyzed. A 1:1 propensity score matching was applied to the assignment of tenofovir–disoproxil–fumarate or entecavir treatment. Changes in serum cholesterol, including oxidized-LDL, were analyzed. Subsequently, in vitro analysis elucidated the mechanism associated with the effect of NAs on lipid metabolism.

Results

Administration of tenofovir–disoproxil–fumarate, not entecavir, to chronic HBV patients, decreased serum cholesterol levels, including non-HDL and oxidized-LDL, which are strongly associated with arteriosclerosis. In vitro analysis revealed that tenofovir–disoproxil–fumarate reduced supernatant cholesterol, and upregulated the scavenger receptor, CD36, in hepatocytes. Meanwhile, silencing of hepatic CD36 increased supernatant cholesterol and negated the cholesterol-reducing effect of tenofovir–disoproxil–fumarate in HepG2-cells. Reporter, microarray, and RT-PCR analyses further revealed that tenofovir–disoproxil–fumarate treatment activates PPAR-α-mediated signaling, and upregulates PPAR-α target genes, including CPT1 and CD36. Alternatively, silencing of PPAR-α reversed the effects of tenofovir–disoproxil–fumarate on CD36.

Conclusions

Tenofovir–disoproxil–fumarate modulates lipid metabolism by upregulating hepatic CD36 via PPAR-α activation. Since dyslipidemia could be associated with arteriosclerosis and hepatocarcinogenesis, these discoveries provide novel insights into anti-HBV therapies, as well as the associated extrahepatic effects of NA.

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Acknowledgements

The authors thank all patients and their families and the investigators and staff of the participating institutions, NORTE Study Group a. The principal investigators of the NORTE study sites are listed below: Tomofumi Takagi (JCHO Sapporo Hokushin Hospital), Atsushi Nagasaka (Sapporo City General Hospital), Akira Fuzinaga (Abashiri-Kosei General Hospital), Hideaki Kikuchi, (Obihiro-Kosei General Hospital), Ken Furuya (JCHO Hokkaido Hospital), Takashi katou (National Hospital Organization Hokkaido Medical Center), Takashi Meguro (Hokkaido Gastroenterology Hospital), Akiyoshi Saga (Kaisei Hospital), Munenori Okamoto (Aiiku Hospital), Masaki Katagiri (Sapporo Hokuyu Hospital), Takuto Miyagishima (Kushiro Rosai Hospital), Jun Konno (Hakodate Central General Hospital), Kenichi Kumagai (Mori city National Health Insurance Hospital), Manabu Onodera (NTT EAST Sapporo Hospital), Tomoe Kobayashi (Tomakomai City Hospital), Minoru Uebayashi (Japanese Red Cross Kitami Hospital), Kanji Katou (Iwamizawa Municipal General Hospital), Yasuyuki Kunieda (Wakkanai City Hospital), Miki Tateyama (Tomakomai Nissho Hospital), Atsuhiko Kawakami (Sapporo Century Hospital), Izumi Tsunematsu (Touei hospital), Keisuke Shinada (Keiwakai Ebetsu Hospital) and Yoshiya Yamamoto (Hakodate Municipal Hospital). We would also like to thank Dr. Koichi Watashi and Dr. Takaji Wakita for generously providing the Hep2.2.15 cells.

Funding

This study was supported in part by Grants from the Japan Agency for Medical Research and Development (AMED; Grant Numbers JP20fk0210072, JP20fk0210064, JP20fk0210056, JP20fk0310101, JP20fk0210047, JP20fk0210048, JP20fk0210058, JP20fk0210066, JP20fk0210067) and SPS KAKENHI (Grant No. 19K08458).

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Author notes

  1. Kazuharu Suzuki and Goki Suda contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan

    Kazuharu Suzuki, Goki Suda, Megumi Kimura, Ren Yamada, Takashi Kitagataya, Koji Yamamoto, Taku Shigesawa, Akihisa Nakamura, Masatsugu Ohara, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi & Naoya Sakamoto

  2. Department of Gastroenterology, Hakodate Municipal Hospital, Hokkaido, Japan

    Yoshiya Yamamoto & Osamu Maehara

  3. Department of Gastroenterology, JCHO Hokkaido Hospital, Hokkaido, Japan

    Ken Furuya & Masaru Baba

  4. Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan

    Akinobu Nakamura

  5. Division of Diabetes and Obesity, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    Hideaki Miyoshi

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  1. Kazuharu Suzuki
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Contributions

KS and GS contributed equally to this work. KS and GS designed this study, performed the statistical analyses, and wrote the manuscript. YY, KF, MB, AN HM, MK,TK, KY, AN MO, NK, MN, TS, MN, KM, KO, and SO, collected the data KS, GS, MK, KY, conducted in vitro experiments. AN, HK, MN, KM, KO, and NS provided hepatological advice and edited the manuscript. MN, SO and NS revised the manuscript for important intellectual content.

Corresponding author

Correspondence to Goki Suda.

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Conflict of interest

Professor Naoya Sakamoto received lecture fees from Bristol Myers Squibb and Pharmaceutical K.K, grants and endowments from MSD K.K and Chugai Pharmaceutical Co., Ltd, and a research grant from Gilead Sciences, Inc. Dr. Goki Suda received research grants from Bristol Myers Squibb, MSD K.K, and Gilead Sciences. The other authors have nothing to disclose.

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Suzuki, K., Suda, G., Yamamoto, Y. et al. Tenofovir–disoproxil–fumarate modulates lipid metabolism via hepatic CD36/PPAR-alpha activation in hepatitis B virus infection. J Gastroenterol 56, 168–180 (2021). https://doi.org/10.1007/s00535-020-01750-3

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