乙型肝炎病毒感染中替诺福韦-二甲环戊酰胺-富马酸酯通过肝

StephenW

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

    Kazuharu Suzuki, Goki Suda, Yoshiya Yamamoto, Ken Furuya, Masaru Baba, Akinobu Nakamura, Hideaki Miyoshi, Megumi Kimura, Osamu Maehara, Ren Yamada, Takashi Kitagataya, Koji Yamamoto, Taku Shigesawa, Akihisa Nakamura, Masatsugu Ohara, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi & Naoya Sakamoto for the NORTE Study Group

Journal of Gastroenterology volume 56, pages168–180(2021)Cite this article

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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.

StephenW

乙型肝炎病毒感染中替诺福韦-二甲环戊酰胺-富马酸酯通过肝CD36 /PPAR-α激活来调节脂质代谢

    铃木和晴（Kazuharu Suzuki），须田悟树（Goki Suda），山本义也（Yoshiya Yamamoto），古谷健（Ken Furuya），马萨鲁·巴巴（Masaru Baba），中村明信（Akinobu Nakamura），三宅秀明（Hideaki Miyoshi），木村惠（Megumi），前卫小原，山田Ren，北高隆，山本浩二，重泽泽（Taku Shigesawa），中久昭久（Nakahisa Nakamura），中井正久（Nasakigu） ，NORTA研究组的Takaya Sho，Tatsuya Sho，Mitsuteru Natsuizaka，森川宪一，小川浩二，大西俊介和坂本直也

胃肠病学杂志第56卷，第168–180页（2021），引用本文

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抽象
背景

恩替卡韦和替诺福韦-二甲酚-富马酸酯是一线核苷酸（NA）类似物（NA），用于治疗乙型肝炎病毒（HBV）感染。但是，长期服用会影响肝外器官。在本文中，我们试图研究NA对脂质代谢的影响，同时也表征相关的机制。
方法

回顾性研究对使用恩替卡韦或替诺福韦-二甲环磷酰胺-富马酸酯的HBV患者进行。分析了患者的临床信息，以及在基线和治疗开始后6-12个月获得的保存的血清样本。 1：1的倾向得分匹配适用于替诺福韦-二甲酚-富马酸盐或恩替卡韦治疗的分配。分析了血清胆固醇的变化，包括氧化的LDL。随后，体外分析阐明了与NAs对脂质代谢的影响有关的机制。
结果

对慢性HBV患者使用替诺福韦-二甲氨蝶呤-富马酸盐而不是恩替卡韦可降低血清胆固醇水平，包括非HDL和氧化型LDL，这与动脉硬化密切相关。体外分析表明，替诺福韦-二甲环戊酰胺-富马酸酯降低了肝细胞上清液的胆固醇水平，并上调了清道夫受体CD36。同时，肝CD36沉默会增加HepG2细胞中上清液的胆固醇含量，并否定替诺福韦-二甲酚-富马酸盐的降胆固醇作用。记者，微阵列和RT-PCR分析进一步表明，替诺福韦-二甲环戊酰胺-富马酸盐治疗可激活PPAR-α介导的信号传导，并上调PPAR-α靶基因，包括CPT1和CD36。另外，沉默PPAR-α可以逆转替诺福韦-二甲环戊酰胺-富马酸酯对CD36的作用。
结论

替诺福韦酯-二甲环戊酰胺-富马酸酯通过PPAR-α激活上调肝CD36来调节脂质代谢。由于血脂异常可能与动脉硬化和肝癌发生有关，因此这些发现为抗HBV治疗以及NA相关的肝外作用提供了新的见解。