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