Sirt1 and Sirt6 mediate beneficial effects of rosiglitazone on hepatic lipid accumulation

PLoS One. 2014 Aug 18;9(8):e105456. doi: 10.1371/journal.pone.0105456. eCollection 2014.

Abstract

Background: Sirtuin (Sirt), a sensor of the cell metabolic state, regulates glucose and lipid metabolism. The aim of this study was to address whether rosiglitazone (RGZ) alters hepatic Sirt1 and whether Sirt1 and/or Sirt6 have a regulatory role in the protective effects of RGZ on hepatocyte steatosis.

Methods: To investigate the effect of RGZ on hepatic Sirt1, rats were administered with RGZ for 6 weeks. The involvement of Sirt1/6 in the RGZ-mediated effect against hepatic steatosis was evaluated by single or double knockdown of Sirt1 and Sirt6 in a hepatocyte steatosis model.

Results: RGZ in vivo increased Sirt1 expression and its activity in rat livers. In a hepatocyte steatosis model, RGZ significantly reduced lipid accumulation and activated the Sirt1/6-LKB1-AMPK pathway. Sirt1 knockdown abolished the effects of RGZ with regard to hepatocyte fat accumulation and the Sirt1/6-LKB1-AMPK pathway, suggesting that Sirt1 is a key regulator of RGZ-mediated metabolic processes. Sirt6 knockdown inhibited the protective effects of RGZ to a lesser extent than Sirt1, and double knockdown of Sirt1/6 showed no synergistic effects.

Conclusion: Our results demonstrate that Sirt1/6 are involved in the RGZ-mediated effects on hepatocyte steatosis, and the regulatory effects of Sirt1 and Sirt6 are not synergistic but compensatory for improving hepatocyte steatosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Fatty Liver / drug therapy*
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Gene Knockdown Techniques
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Lipid Metabolism / drug effects*
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Mice
  • Rats
  • Rosiglitazone
  • Signal Transduction / drug effects
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Thiazolidinediones / pharmacology
  • Thiazolidinediones / therapeutic use*

Substances

  • Hypoglycemic Agents
  • Thiazolidinediones
  • Rosiglitazone
  • Sirtuin 1
  • Sirtuins
  • sirtuin 6, rat

Grants and funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A2009143 to C-Y.P. and 2012R1A1A1004861 to S.J.Y.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.