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
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DOI：
10.1007/s00535-020-01750-3
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发表时间：
2020-11-19
影响因子：
6.3
通讯作者：
Sakamoto, Naoya
中科院分区：
文献类型：
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作者：
Suzuki, Kazuharu;Suda, Goki;Sakamoto, Naoya
背景恩替卡韦和替诺福韦-二异丙酯-富马酸盐是治疗B型肝炎病毒（HBV）感染的一线核苷（酸）类似物（NA）;然而，长期给药可能影响肝外器官。在此，我们试图研究NA对脂质代谢的影响，同时也表征了相关的机制。方法回顾性分析恩替卡韦和富马酸替诺福韦酯治疗乙型肝炎患者的临床资料。分析患者临床信息以及在基线和治疗开始后6-12个月获得的保存血清样本。采用1：1倾向评分匹配分配替诺福韦-地索西尔-富马酸酯或恩替卡韦治疗。分析血清胆固醇（包括氧化LDL）的变化。随后，体外分析阐明了与NAs对脂质代谢的影响相关的机制。结果：替诺福韦-二异戊酰-富马酸酯，而不是恩替卡韦，慢性HBV患者的管理，降低血清胆固醇水平，包括非HDL和氧化LDL，这是强烈相关的动脉硬化。体外分析显示，替诺福韦-二异山梨醇-富马酸盐降低上清液胆固醇，并上调肝细胞中的清道夫受体CD 36。同时，肝脏CD 36的沉默增加了上清液胆固醇，并否定了替诺福韦-二异山梨醇-富马酸酯在HepG 2-细胞中的降胆固醇作用。报告基因、微阵列和RT-PCR分析进一步揭示，替诺福韦-二异山梨醇-富马酸酯处理激活了PPAR-alpha介导的信号传导，并上调了PPAR-alpha靶基因，包括CPT 1和CD 36。或者，PPAR-a的沉默逆转了替诺福韦-二异山梨醇-富马酸盐对CD 36的作用。结论富马酸替诺福韦酯通过激活PPAR-alpha上调肝脏CD 36调节脂代谢。由于血脂异常可能与动脉硬化和肝癌发生有关，这些发现为抗HBV治疗以及NA的相关肝外效应提供了新的见解。
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-alpha-mediated signaling, and upregulates PPAR-alpha target genes, including CPT1 and CD36. Alternatively, silencing of PPAR-alpha reversed the effects of tenofovir-disoproxil-fumarate on CD36. Conclusions Tenofovir-disoproxil-fumarate modulates lipid metabolism by upregulating hepatic CD36 via PPAR-alpha 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.