Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats

• Published in: PloS one Vol. 6; no. 2; p. e17057
• Main Authors: Yang, Soo Jin, Choi, Jung Mook, Chae, Seoung Wan, Kim, Won Jun, Park, Se Eun, Rhee, Eun Jung, Lee, Won Young, Oh, Ki Won, Park, Sung Woo, Kim, Sun Woo, Park, Cheol-Young
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.02.2011; Public Library of Science (PLoS)
• Subjects: Accumulation; Activation; AMP; AMP-activated protein kinase; Animals; Biology; Cells, Cultured; Drug Evaluation, Preclinical; Fatty acids; Fatty liver; Fatty Liver - drug therapy; Fatty Liver - genetics; Fatty Liver - metabolism; Fatty Liver - pathology; Forkhead protein; FOXO1 protein; Gene expression; Gene Expression Regulation, Enzymologic - drug effects; Glucose; Hepatocytes; Hypolipidemic Agents - pharmacology; Insulin resistance; Kinases; Lipid metabolism; Lipid Metabolism - drug effects; Lipid Metabolism - genetics; Liver; Liver - drug effects; Liver - metabolism; LKB1 protein; Male; Medicine; Metabolism; Mice; mRNA; Phosphorylation; Physiological aspects; PPAR gamma - agonists; PPAR gamma - metabolism; Rats; Rats, Inbred OLETF; Rats, Long-Evans; RNA; Rodents; Rosiglitazone; Sirtuins - genetics; Sirtuins - metabolism; Sirtuins - physiology; Steatosis; Stomach; Thiazolidinediones; Thiazolidinediones - pharmacology; Thiazolidinediones - therapeutic use; Triglycerides
• DOI: 10.1371/journal.pone.0017057
• ISSN: 1932-6203

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.