2. Academic Validation
  3. 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. [email protected].
  • 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.
PMID: 33211179 DOI: 10.1007/s00535-020-01750-3
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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