Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats.
BACKGROUND: 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. METHODS: To investigate the effect of...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3044155?pdf=render |
| _version_ | 1828367631722217472 |
|---|---|
| author | Soo Jin Yang Jung Mook Choi Seoung Wan Chae Won Jun Kim Se Eun Park Eun Jung Rhee Won Young Lee Ki Won Oh Sung Woo Park Sun Woo Kim Cheol-Young Park |
| author_facet | Soo Jin Yang Jung Mook Choi Seoung Wan Chae Won Jun Kim Se Eun Park Eun Jung Rhee Won Young Lee Ki Won Oh Sung Woo Park Sun Woo Kim Cheol-Young Park |
| author_sort | Soo Jin Yang |
| collection | DOAJ |
| description | BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. |
| first_indexed | 2024-04-14T06:00:25Z |
| format | Article |
| id | doaj.art-06e8c769dfa346e3bfc038b639de29f6 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-14T06:00:25Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-06e8c769dfa346e3bfc038b639de29f62022-12-22T02:08:47ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0162e1705710.1371/journal.pone.0017057Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats.Soo Jin YangJung Mook ChoiSeoung Wan ChaeWon Jun KimSe Eun ParkEun Jung RheeWon Young LeeKi Won OhSung Woo ParkSun Woo KimCheol-Young ParkBACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.http://europepmc.org/articles/PMC3044155?pdf=render |
| spellingShingle | Soo Jin Yang Jung Mook Choi Seoung Wan Chae Won Jun Kim Se Eun Park Eun Jung Rhee Won Young Lee Ki Won Oh Sung Woo Park Sun Woo Kim Cheol-Young Park Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats. PLoS ONE |
| title | Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats. |
| title_full | Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats. |
| title_fullStr | Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats. |
| title_full_unstemmed | Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats. |
| title_short | Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats. |
| title_sort | activation of peroxisome proliferator activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats |
| url | http://europepmc.org/articles/PMC3044155?pdf=render |
| work_keys_str_mv | AT soojinyang activationofperoxisomeproliferatoractivatedreceptorgammabyrosiglitazoneincreasessirt6expressionandameliorateshepaticsteatosisinrats AT jungmookchoi activationofperoxisomeproliferatoractivatedreceptorgammabyrosiglitazoneincreasessirt6expressionandameliorateshepaticsteatosisinrats AT seoungwanchae activationofperoxisomeproliferatoractivatedreceptorgammabyrosiglitazoneincreasessirt6expressionandameliorateshepaticsteatosisinrats AT wonjunkim activationofperoxisomeproliferatoractivatedreceptorgammabyrosiglitazoneincreasessirt6expressionandameliorateshepaticsteatosisinrats AT seeunpark activationofperoxisomeproliferatoractivatedreceptorgammabyrosiglitazoneincreasessirt6expressionandameliorateshepaticsteatosisinrats AT eunjungrhee activationofperoxisomeproliferatoractivatedreceptorgammabyrosiglitazoneincreasessirt6expressionandameliorateshepaticsteatosisinrats AT wonyounglee activationofperoxisomeproliferatoractivatedreceptorgammabyrosiglitazoneincreasessirt6expressionandameliorateshepaticsteatosisinrats AT kiwonoh activationofperoxisomeproliferatoractivatedreceptorgammabyrosiglitazoneincreasessirt6expressionandameliorateshepaticsteatosisinrats AT sungwoopark activationofperoxisomeproliferatoractivatedreceptorgammabyrosiglitazoneincreasessirt6expressionandameliorateshepaticsteatosisinrats AT sunwookim activationofperoxisomeproliferatoractivatedreceptorgammabyrosiglitazoneincreasessirt6expressionandameliorateshepaticsteatosisinrats AT cheolyoungpark activationofperoxisomeproliferatoractivatedreceptorgammabyrosiglitazoneincreasessirt6expressionandameliorateshepaticsteatosisinrats |