Diabetes Research Institute, Sungkyunkwan University School of Medicine, Kangbuk Samsung Hospital, Seoul, Korea.
PLoS One. 2011 Feb 23;6(2):e17057. doi: 10.1371/journal.pone.0017057.
Sirt6 has been implicated in the regulation of hepatic lipid metabolism and the development of hepatic steatosis. The aim of this study was to address the potential role of Sirt6 in the protective effects of rosiglitazone (RGZ) on hepatic steatosis.
To investigate the effect of RGZ on hepatic steatosis, rats were treated with RGZ (4 mg·kg⁻¹·day⁻¹) by stomach gavage for 6 weeks. The involvement of Sirt6 in the RGZ's regulation was evaluated by Sirt6 knockdown in AML12 mouse hepatocytes.
RGZ treatment ameliorated hepatic lipid accumulation and increased expression of Sirt6, peroxisome proliferator-activated receptor gamma coactivtor-1-α (Ppargc1a/PGC1-α) and Forkhead box O1 (Foxo1) in rat livers. AMP-activated protein kinase (AMPK) phosphorylation was also increased by RGZ, accompanied by alterations in phosphorylation of LKB1. Interestingly, in free fatty acid-treated cells, Sirt6 knockdown increased hepatocyte lipid accumulation measured as increased triglyceride contents (p = 0.035), suggesting that Sirt6 may be beneficial in reducing hepatic fat accumulation. In addition, Sirt6 knockdown abolished the effects of RGZ on hepatocyte fat accumulation, mRNA and protein expression of Ppargc1a/PGC1-α and Foxo1, and phosphorylation levels of LKB1 and AMPK, suggesting that Sirt6 is involved in RGZ-mediated metabolic effects.
Our results demonstrate that RGZ significantly decreased hepatic lipid accumulation, and that this process appeared to be mediated by the activation of the Sirt6-AMPK pathway. We propose Sirt6 as a possible therapeutic target for hepatic steatosis.
Sirt6 参与调节肝脏脂质代谢和肝脂肪变性的发生。本研究旨在探讨 Sirt6 在罗格列酮（RGZ）对肝脂肪变性的保护作用中的潜在作用。
为了研究 RGZ 对肝脂肪变性的影响，通过灌胃给予大鼠 RGZ（4 mg·kg⁻¹·天⁻¹）6 周。通过 AML12 小鼠肝细胞中的 Sirt6 敲低来评估 Sirt6 在 RGZ 调节中的作用。
RGZ 治疗可改善肝脂质蓄积，并增加大鼠肝脏中 Sirt6、过氧化物酶体增殖物激活受体γ共激活因子 1-α（Ppargc1a/PGC1-α）和叉头框 O1（Foxo1）的表达。RGZ 还增加了 AMP 激活的蛋白激酶（AMPK）磷酸化，同时改变了 LKB1 的磷酸化。有趣的是，在游离脂肪酸处理的细胞中，Sirt6 敲低增加了肝细胞脂质蓄积，表现为甘油三酯含量增加（p=0.035），表明 Sirt6 可能有利于减少肝脂肪蓄积。此外，Sirt6 敲低消除了 RGZ 对肝细胞脂肪蓄积、Ppargc1a/PGC1-α 和 Foxo1 的 mRNA 和蛋白表达以及 LKB1 和 AMPK 磷酸化水平的影响，表明 Sirt6 参与了 RGZ 介导的代谢作用。
我们的结果表明，RGZ 可显著减少肝脂质蓄积，这一过程似乎是通过激活 Sirt6-AMPK 途径介导的。我们提出 Sirt6 可能是肝脂肪变性的潜在治疗靶点。
