Kondo Yoshitaka, Hasegawa Goji, Okada Hiroshi, Senmaru Takafumi, Fukui Michiaki, Nakamura Naoto, Sawada Morio, Kitawaki Jo, Okanoue Takeshi, Kishimoto Yuki, Amano Akiko, Maruyama Naoki, Obayashi Hiroshi, Ishigami Akihito
Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
PLoS One. 2013 Jun 3;8(6):e65698. doi: 10.1371/journal.pone.0065698. Print 2013.
BACKGROUND/AIMS: The senescence marker protein-30 (SMP30) is a 34 kDa protein originally identified in rat liver that shows decreased levels with age. Several functional studies using SMP30 knockout (Smp30(Y/-) ) mice established that SMP30 functions as an antioxidant and protects against apoptosis. To address the potential role of SMP30 in nonalcoholic fatty liver disease (NAFLD) pathogenesis, we established Smp30(Y/-) mice on a Lepr(db/db) background (Lepr(db/db)Smp30(Y/-) mice). RESEARCH DESIGN/PRINCIPAL FINDINGS: Male Lepr(db/db)Smp30(Y/-) mice were fed a standard diet (340 kcal/100 g, fat 5.6%) for 16 weeks whereupon the lipid/lipoprotein profiles, hepatic expression of genes related to lipid metabolism and endoplasmic reticulum stress markers were analyzed by HPLC, quantitative RT-PCR and western blotting, respectively. Changes in the liver at a histological level were also investigated. The amount of SMP30 mRNA and protein in livers was decreased in Lepr(db/db)Smp30(Y/+) mice compared with Lepr(db/+)Smp30(Y/+) mice. Compared with Lepr(db/db)Smp30(Y/+) mice, 24 week old Lepr(db/db)Smp30(Y/-) mice showed: i) increased small dense LDL-cho and decreased HDL-cho levels; ii) fatty liver accompanied by numerous inflammatory cells and increased oxidative stress; iii) decreased mRNA expression of genes involved in fatty acid oxidation (PPARα) and lipoprotein uptake (LDLR and VLDLR) but increased CD36 levels; and iv) increased endoplasmic reticulum stress.
Our data strongly suggest that SMP30 is closely associated with NAFLD pathogenesis, and might be a possible therapeutic target for NAFLD.
背景/目的：衰老标记蛋白-30（SMP30）是一种最初在大鼠肝脏中发现的34 kDa蛋白，其水平随年龄增长而降低。几项使用SMP30基因敲除（Smp30(Y/-)）小鼠的功能研究证实，SMP30具有抗氧化功能并可防止细胞凋亡。为了研究SMP30在非酒精性脂肪性肝病（NAFLD）发病机制中的潜在作用，我们构建了Lepr(db/db)背景的Smp30(Y/-)小鼠（Lepr(db/db)Smp30(Y/-)小鼠）。
研究设计/主要发现：雄性Lepr(db/db)Smp30(Y/-)小鼠喂食标准饮食（340千卡/100克，脂肪5.6%）16周，随后分别通过高效液相色谱法（HPLC）、定量逆转录-聚合酶链反应（qRT-PCR）和蛋白质印迹法分析脂质/脂蛋白谱、脂质代谢相关基因的肝脏表达以及内质网应激标志物。还研究了肝脏在组织学水平的变化。与Lepr(db/+)Smp30(Y/+)小鼠相比，Lepr(db/db)Smp30(Y/+)小鼠肝脏中SMP30 mRNA和蛋白的量减少。与Lepr(db/db)Smp30(Y/+)小鼠相比，24周龄的Lepr(db/db)Smp30(Y/-)小鼠表现出：i）小而密的低密度脂蛋白胆固醇（LDL-cho）增加，高密度脂蛋白胆固醇（HDL-cho）水平降低；ii）脂肪肝伴有大量炎性细胞且氧化应激增加；iii）参与脂肪酸氧化（PPARα）和脂蛋白摄取（LDLR和VLDLR）的基因mRNA表达降低，但CD36水平升高；iv）内质网应激增加。
我们的数据强烈表明，SMP30与NAFLD发病机制密切相关，可能是NAFLD的一个潜在治疗靶点。
