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
  • 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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