1. Academic Validation
  2. Tenofovir-disoproxil-fumarate modulates lipid metabolism via hepatic CD36/PPAR-alpha activation in hepatitis B virus infection

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

  • J Gastroenterol. 2021 Feb;56(2):168-180. doi: 10.1007/s00535-020-01750-3.
Kazuharu Suzuki  # 1 Goki Suda  # 2 Yoshiya Yamamoto 3 Ken Furuya 4 Masaru Baba 4 Akinobu Nakamura 5 Hideaki Miyoshi 6 Megumi Kimura 1 Osamu Maehara 3 Ren Yamada 1 Takashi Kitagataya 1 Koji Yamamoto 1 Taku Shigesawa 1 Akihisa Nakamura 1 Masatsugu Ohara 1 Naoki Kawagishi 1 Masato Nakai 1 Takuya Sho 1 Mitsuteru Natsuizaka 1 Kenichi Morikawa 1 Koji Ogawa 1 Shunsuke Ohnishi 1 Naoya Sakamoto 1 NORTE Study Group
Affiliations

Affiliations

  • 1 Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
  • 2 Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. gsudgast@pop.med.hokudai.ac.jp.
  • 3 Department of Gastroenterology, Hakodate Municipal Hospital, Hokkaido, Japan.
  • 4 Department of Gastroenterology, JCHO Hokkaido Hospital, Hokkaido, Japan.
  • 5 Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
  • 6 Division of Diabetes and Obesity, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
  • # Contributed equally.
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.

Keywords

CD36; Hepatitis B virus; Lipid metabolism; Oxidized LDL; PPAR-alpha.

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