Liver-Specific Nonviral Gene Delivery of Fibroblast Growth Factor 21 Protein Expression in Mice Regulates Body Mass and White/Brown Fat Respiration.
Liver-Specific Nonviral Gene Delivery of Fibroblast Growth Factor 21 Protein Expression in Mice Regulates Body Mass and White/Brown Fat Respiration.
复制标题
DOI：
10.1124/jpet.121.000514
复制
发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Elferink CJ
中科院分区：
文献类型：
--
作者：
Girer NG;Rontoyanni VG;Joshi A;Patrikeev I;Murton AJ;Porter C;Motamedi M;Elferink CJ
病毒介导的体内基因递送方法目前在临床和实验环境中的治疗策略中占主导地位，尽管具有由免疫学约束引起的有据可查的限制。在这项研究中，我们证明了非病毒亲肝性体内基因传递的非包装表达构建体，包括编码成纤维细胞生长因子21（FGF 21）的效用。FGF 21是一种重要的肝细胞因子，其表达与各种肥胖动物模型的治疗结果呈正相关。我们的数据表明，在单次注射FGF 21表达质粒后，FGF 21表达可以在免疫活性FGF 21敲除小鼠的肝脏中恢复至少2周。在野生型C57 BL 6/J小鼠中，体内转染表达FGF 21的质粒诱导体重减轻，减少肥胖，并在2周内激活白色脂肪中的产热作用。此外，体内FGF 21基因递送通过减少肥胖和增加棕色脂肪中的解偶联蛋白1依赖性产热以及通过增强皮下和性腺周围白色脂肪中的呼吸能力来保护C57 BL 6/J小鼠免受饮食诱导的肥胖。总之，这些数据说明了一种简单有效的方法，用于将延长的蛋白质表达特异性地递送到肝脏。我们认为，这种方法将在基础科学研究中找到实用性，作为一种实用的手段，以加强体内研究表征肝脏蛋白质功能。我们进一步相信我们的数据为进一步探索非病毒基因治疗在小鼠疾病模型中的潜在临床应用提供了理论基础。这项研究提出了一种有价值的方法，非病毒基因传递在小鼠中，改善了现有的技术。这些数据为进一步探索非病毒基因治疗在小鼠疾病模型中的潜在临床应用提供了理论基础，并可能增强表征肝脏蛋白功能的体内研究。
Viral-mediated in vivo gene delivery methods currently dominate among therapeutic strategies within the clinical and experimental settings, albeit with well documented limitations arising from immunologic constraints. In this study, we demonstrate the utility of nonviral hepatotropic in vivo gene delivery of unpackaged expression constructs, including one encoding fibroblast growth factor 21 (FGF21). FGF21 is an important hepatokine whose expression positively correlates with therapeutic outcomes across various animal models of obesity. Our data demonstrate that FGF21 expression can be restored into the livers of immunocompetent FGF21 knockout mice for at least 2 weeks after a single injection with an FGF21 expression plasmid. In wild-type C57BL6/J mice, in vivo transfection with an FGF21-expressing plasmid induced weight loss, decreased adiposity, and activated thermogenesis in white fat within 2 weeks. Furthermore, in vivo FGF21 gene delivery protected C57BL6/J mice against diet-induced obesity by decreasing adiposity and increasing uncoupling protein 1–dependent thermogenesis in brown fat and by boosting respiratory capacity in subcutaneous and perigonadal white fat. Together, the data illustrate a facile and effective methodology for delivering prolonged protein expression specifically to the liver. We contend that this method will find utility in basic science research as a practical means to enhance in vivo studies characterizing liver protein function. We further believe our data provide a rationale for further exploring the potential clinical utility of nonviral gene therapy in mouse models of disease. This study presents a valuable method for nonviral gene delivery in mice that improves upon existing techniques. The data provide a rationale for further exploring the potential clinical utility of nonviral gene therapy in mouse models of disease and will likely enhance in vivo studies characterizing liver protein function.
登录
查看更多内容
DOI：
10.1016/j.bbrc.2007.06.068
发表时间：
2007-08-24
影响因子：
3.1
作者：
Lundasen, Thomas;Hunt, Mary C.;Rudling, Mats
通讯作者：
Rudling, Mats
成纤维细胞生长因子 21 受未折叠蛋白反应的 IRE1 α-XBP1 分支调节并抵消内质网应激诱导的肝脂肪变性
影响因子：
4.8
作者：
Jiang, Shan;Yan, Cheng;Jia, Wei-ping
通讯作者：
Jia, Wei-ping
循环的FGF21是肝脏的，并在进食和过度喂养过程中增强了葡萄糖的摄取。
影响因子：
7.7
作者：
Markan KR;Naber MC;Ameka MK;Anderegg MD;Mangelsdorf DJ;Kliewer SA;Mohammadi M;Potthoff MJ
通讯作者：
Potthoff MJ
影响因子：
7.7
作者：
Xu J;Lloyd DJ;Hale C;Stanislaus S;Chen M;Sivits G;Vonderfecht S;Hecht R;Li YS;Lindberg RA;Chen JL;Jung DY;Zhang Z;Ko HJ;Kim JK;Véniant MM
通讯作者：
Véniant MM
DOI：
10.1073/pnas.93.20.10887
发表时间：
1996-10-01
影响因子：
11.1
作者：
Feil, R;Brocard, J;Chambon, P
通讯作者：
Chambon, P