Knockdown of hepatocyte Perilipin-3 mitigates hepatic steatosis and steatohepatitis caused by hepatocyte CGI-58 deletion in mice.
Knockdown of hepatocyte Perilipin-3 mitigates hepatic steatosis and steatohepatitis caused by hepatocyte CGI-58 deletion in mice.
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敲除肝细胞 Perilipin-3 可减轻小鼠肝细胞 CGI-58 缺失引起的肝脂肪变性和脂肪性肝炎
DOI：
10.1093/jmcb/mjac055
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发表时间：
2022-12-26
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
比较基因鉴定-58 (CGI-58)，也被称为含有α/β水解酶结构域5，是脂肪甘油三酯脂肪酶的协同激活剂，可水解储存在细胞质脂滴中的甘油三酯。CGI-58基因突变导致Chanarin-Dorfman综合征（CDS），一种常染色体隐性中性脂质储存病伴鱼鳞病。CDS的肝脏病理表现为脂肪变性和脂肪性肝炎，目前尚无有效的治疗方法。Perilipin-3 （Plin3）是Perilipin-ADRP-TIP47蛋白家族的成员，对脂滴的生物形成至关重要。本研究的目的是验证一个假设，即主要脂滴蛋白的缺失减轻了肝细胞CGI-58缺乏引起的脂肪肝发病机制。在肝细胞特异性启动子的控制下，给成年cgi -58小鼠注射同时表达Cre重组酶和靶向Plin3的microRNA的腺相关载体，然后饲喂高脂饲料6周。然后从这些动物身上采集肝脏和血液样本进行组织学和生化分析。肝细胞Plin3敲低可预防肝细胞CGI-58缺乏引起的脂肪变性、脂肪性肝炎和坏死性坏死。我们的研究首次表明，抑制肝细胞中的Plin3足以减轻小鼠肝细胞CGI-58缺陷引起的肝脂肪变性和脂肪性肝炎。
Comparative gene identification-58 (CGI-58), also known as α/β hydrolase domain containing 5, is the co-activator of adipose triglyceride lipase that hydrolyzes triglycerides stored in the cytosolic lipid droplets. Mutations in CGI-58 gene cause Chanarin–Dorfman syndrome (CDS), an autosomal recessive neutral lipid storage disease with ichthyosis. The liver pathology of CDS manifests as steatosis and steatohepatitis, which currently has no effective treatments. Perilipin-3 (Plin3) is a member of the Perilipin–ADRP–TIP47 protein family that is essential for lipid droplet biogenesis. The objective of this study was to test a hypothesis that deletion of a major lipid droplet protein alleviates fatty liver pathogenesis caused by CGI-58 deficiency in hepatocytes. Adult CGI-58-floxed mice were injected with adeno-associated vectors simultaneously expressing the Cre recombinase and microRNA against Plin3 under the control of a hepatocyte-specific promoter, followed by high-fat diet feeding for 6 weeks. Liver and blood samples were then collected from these animals for histological and biochemical analysis. Plin3 knockdown in hepatocytes prevented steatosis, steatohepatitis, and necroptosis caused by hepatocyte CGI-58 deficiency. Our work is the first to show that inhibiting Plin3 in hepatocytes is sufficient to mitigate hepatocyte CGI-58 deficiency-induced hepatic steatosis and steatohepatitis in mice.
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影响因子：
11.8
作者：
Mejhert, Niklas;Gabriel, Katlyn R.;Frendo-Cumbo, Scott;Krahmer, Natalie;Song, Jiunn;Kuruvilla, Leena;Chitraju, Chandramohan;Boland, Sebastian;Jang, Dong-Keun;von Grotthuss, Marcin;Costanzo, Maria C.;Ryden, Mikael;Olzmann, James A.;Flannick, Jason;Burtt, Noel P.;Farese, Robert V., Jr.;Walther, Tobias C.
通讯作者：
Walther, Tobias C.
影响因子：
16.6
作者：
Gallardo-Montejano VI;Saxena G;Kusminski CM;Yang C;McAfee JL;Hahner L;Hoch K;Dubinsky W;Narkar VA;Bickel PE
通讯作者：
Bickel PE
影响因子：
6.5
作者：
Brown, J. Mark;Betters, Jenna L.;Yu, Liqing
通讯作者：
Yu, Liqing
DOI：
10.1152/ajpgi.90204.2008
发表时间：
2008-09-01
影响因子：
4.5
作者：
Varela, Gladys M.;Antwi, Daniel A.;Ahima, Rexford S.
通讯作者：
Ahima, Rexford S.
影响因子：
13.3
作者：
Tsai, Tsung-Huang;Chen, Elaine;Chang, Benny Hung-Junn
通讯作者：
Chang, Benny Hung-Junn