乙型肝炎病毒感染中替諾福韋-disoproxil-富馬酸酯可通過肝CD36

StephenW

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.

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

StephenW

乙型肝炎病毒感染中替諾福韋-disoproxil-富馬酸酯可通過肝CD36 /PPAR-α激活來調節脂質代謝
鈴木和晴1，五木須田2，山本芳也3，谷谷健4，丸正麻巴4，中村明信5，三好英樹6，木村惠美1，前原小寒3，蓮山田1，北谷孝史1，山本浩司1，Shi澤卓1，中村明久1，大原正久1，川木直樹1，中本正人1，卓也Sho 1，宮中滿照1，森川憲一1，小川晃司1，大西俊介1，坂本直也1，NORTE學習小組
隸屬關係
隸屬關係

    1個
    日本北海道札幌市北區北7西15號北海道大學醫學研究生院胃腸病學和肝病學系，060-8638，日本。
    2
    日本北海道札幌市北區北7西15號北海道大學醫學研究生院胃腸病學和肝病學系，060-8638，日本。 [email protected]。
    3
    日本北海道函館市立醫院消化內科。
    4
    日本北海道JCHO北海道醫院消化內科。
    5
    日本北海道大學醫學部，醫學研究生院風濕病學，內分泌和腎髒病學系。
    6
    日本札幌市北海道大學醫學院醫學研究科糖尿病與肥胖學系。

    PMID：33211179 DOI：10.1007 / s00535-020-01750-3

抽象

背景：恩替卡韋和替諾福韋-二氫吡庫胺-富馬酸酯是用於治療乙型肝炎病毒（HBV）感染的一線核苷酸（NA）類似物。但是，長期服用會影響肝外器官。在本文中，我們試圖研究NA對脂質代謝的影響，同時也表徵相關的機制。

方法：回顧性研究對接受恩替卡韋或替諾福韋-二吡呋酯-富馬酸鹽治療的HBV患者進行。分析了患者的臨床信息以及在治療開始和治療開始後的6-12個月獲得的血清樣本。 1：1傾向得分匹配適用於替諾福韋-二甲吡唑-富馬酸酯或恩替卡韋治療的分配。分析了血清膽固醇的變化，包括氧化的LDL。隨後，體外分析闡明了與NAs對脂質代謝的影響有關的機制。

結果：對慢性HBV患者使用替諾福韋-二甲吡嗪-富馬酸鹽而非恩替卡韋，可降低血清膽固醇水平，包括非HDL和氧化型LDL，這與動脈硬化密切相關。體外分析表明，替諾福韋-二甲氧呋喃富馬酸酯降低了肝細胞中的上清液膽固醇，並上調了清道夫受體CD36。同時，肝CD36沉默增加了HepG2細胞中上清液的膽固醇水平，並否定了替諾福韋-二甲酚-富馬酸酯的降膽固醇作用。記者，微陣列和RT-PCR分析進一步顯示，替諾福韋-二甲吡嗪-富馬酸鹽處理可激活PPAR-α介導的信號傳導，並上調PPAR-α靶基因，包括CPT1和CD36。另外，沉默PPAR-α可以逆轉替諾福韋-二甲吡唑-富馬酸酯對CD36的作用。

結論：替諾福韋-二甲酚-富馬酸酯可通過PPAR-α激活上調肝CD36來調節脂質代謝。由於血脂異常可能與動脈硬化和肝癌發生有關，因此這些發現為抗HBV治療以及NA相關的肝外作用提供了新的見解。

關鍵字：CD36；乙型肝炎病毒;脂質代謝氧化的低密度脂蛋白; PPAR-α。