Activation of free fatty acid receptor 1 improves hepatic steatosis through a p38-dependent pathway

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Abstract

Hepatic steatosis is highly correlated with insulin resistance and diabetes. Although, it has been demonstrated that activation of free fatty acid receptor 1 (FFAR1) by agonists showed benefits for the improvement of diabetes, the effects of FFAR1 agonists on hepatic steatosis were unknown. In this study, a high fat diet (HFD)-induced hepatic steatosis animal model was utilized to evaluate the effects of an FFAR1 agonist, GW9508, on hepatic lipid accumulation, and HepG2 hepatoma cells were also used to clarify the possible mechanisms. Administration of GW9508 significantly decreased the hepatic lipid accumulation with decreased expressions of lipogenesis-related proteins in HFD mice. Knockdown of hepatic Ffar1 by lentiviral vectors containing short hairpin RNA targeted to Ffar1 diminished the effect of GW9508 in HFD mice. In addition, GW9508 decreased oleic acid-induced lipid accumulation in HepG2 cells by decreases in the expression of lipogenesis-related proteins. Moreover, GW9508 downregulated the expression of sterol regulatory element-binding protein 1 (SREBP1) through a p38-dependent pathway, whereas knockdown of Ffar1 in HepG2 cells diminished the effect of GW9508 on the decrease in SREBP1. Considering all these results together, GW9508 exerts a therapeutic effect to improve hepatic steatosis through a p38-dependent pathway. Thus, investigation of chemicals that act on FFAR1 might be a new strategy for the treatment of hepatic steatosis.

Original languageEnglish
Pages (from-to)165-174
Number of pages10
JournalJournal of Molecular Endocrinology
Volume53
Issue number2
DOIs
Publication statusPublished - 2014 Jul 9

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Nonesterified Fatty Acids
Liver
Hep G2 Cells
High Fat Diet
Sterol Regulatory Element Binding Protein 1
Lipogenesis
Lipids
Therapeutic Uses
Oleic Acid
GW9508
Small Interfering RNA
Insulin Resistance
Hepatocellular Carcinoma
Proteins
Down-Regulation
Animal Models

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

Cite this

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title = "Activation of free fatty acid receptor 1 improves hepatic steatosis through a p38-dependent pathway",
abstract = "Hepatic steatosis is highly correlated with insulin resistance and diabetes. Although, it has been demonstrated that activation of free fatty acid receptor 1 (FFAR1) by agonists showed benefits for the improvement of diabetes, the effects of FFAR1 agonists on hepatic steatosis were unknown. In this study, a high fat diet (HFD)-induced hepatic steatosis animal model was utilized to evaluate the effects of an FFAR1 agonist, GW9508, on hepatic lipid accumulation, and HepG2 hepatoma cells were also used to clarify the possible mechanisms. Administration of GW9508 significantly decreased the hepatic lipid accumulation with decreased expressions of lipogenesis-related proteins in HFD mice. Knockdown of hepatic Ffar1 by lentiviral vectors containing short hairpin RNA targeted to Ffar1 diminished the effect of GW9508 in HFD mice. In addition, GW9508 decreased oleic acid-induced lipid accumulation in HepG2 cells by decreases in the expression of lipogenesis-related proteins. Moreover, GW9508 downregulated the expression of sterol regulatory element-binding protein 1 (SREBP1) through a p38-dependent pathway, whereas knockdown of Ffar1 in HepG2 cells diminished the effect of GW9508 on the decrease in SREBP1. Considering all these results together, GW9508 exerts a therapeutic effect to improve hepatic steatosis through a p38-dependent pathway. Thus, investigation of chemicals that act on FFAR1 might be a new strategy for the treatment of hepatic steatosis.",
author = "Horng-Yih Ou and Wu, {Hung Tsung} and Feng-Hwa Lu and Su, {Yu Chu} and Hao-Chang Hung and Jin-Shang Wu and Yi-Ching Yang and Chao-Liang Wu and Chih-Jen Chang",
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T1 - Activation of free fatty acid receptor 1 improves hepatic steatosis through a p38-dependent pathway

AU - Ou, Horng-Yih

AU - Wu, Hung Tsung

AU - Lu, Feng-Hwa

AU - Su, Yu Chu

AU - Hung, Hao-Chang

AU - Wu, Jin-Shang

AU - Yang, Yi-Ching

AU - Wu, Chao-Liang

AU - Chang, Chih-Jen

PY - 2014/7/9

Y1 - 2014/7/9

N2 - Hepatic steatosis is highly correlated with insulin resistance and diabetes. Although, it has been demonstrated that activation of free fatty acid receptor 1 (FFAR1) by agonists showed benefits for the improvement of diabetes, the effects of FFAR1 agonists on hepatic steatosis were unknown. In this study, a high fat diet (HFD)-induced hepatic steatosis animal model was utilized to evaluate the effects of an FFAR1 agonist, GW9508, on hepatic lipid accumulation, and HepG2 hepatoma cells were also used to clarify the possible mechanisms. Administration of GW9508 significantly decreased the hepatic lipid accumulation with decreased expressions of lipogenesis-related proteins in HFD mice. Knockdown of hepatic Ffar1 by lentiviral vectors containing short hairpin RNA targeted to Ffar1 diminished the effect of GW9508 in HFD mice. In addition, GW9508 decreased oleic acid-induced lipid accumulation in HepG2 cells by decreases in the expression of lipogenesis-related proteins. Moreover, GW9508 downregulated the expression of sterol regulatory element-binding protein 1 (SREBP1) through a p38-dependent pathway, whereas knockdown of Ffar1 in HepG2 cells diminished the effect of GW9508 on the decrease in SREBP1. Considering all these results together, GW9508 exerts a therapeutic effect to improve hepatic steatosis through a p38-dependent pathway. Thus, investigation of chemicals that act on FFAR1 might be a new strategy for the treatment of hepatic steatosis.

AB - Hepatic steatosis is highly correlated with insulin resistance and diabetes. Although, it has been demonstrated that activation of free fatty acid receptor 1 (FFAR1) by agonists showed benefits for the improvement of diabetes, the effects of FFAR1 agonists on hepatic steatosis were unknown. In this study, a high fat diet (HFD)-induced hepatic steatosis animal model was utilized to evaluate the effects of an FFAR1 agonist, GW9508, on hepatic lipid accumulation, and HepG2 hepatoma cells were also used to clarify the possible mechanisms. Administration of GW9508 significantly decreased the hepatic lipid accumulation with decreased expressions of lipogenesis-related proteins in HFD mice. Knockdown of hepatic Ffar1 by lentiviral vectors containing short hairpin RNA targeted to Ffar1 diminished the effect of GW9508 in HFD mice. In addition, GW9508 decreased oleic acid-induced lipid accumulation in HepG2 cells by decreases in the expression of lipogenesis-related proteins. Moreover, GW9508 downregulated the expression of sterol regulatory element-binding protein 1 (SREBP1) through a p38-dependent pathway, whereas knockdown of Ffar1 in HepG2 cells diminished the effect of GW9508 on the decrease in SREBP1. Considering all these results together, GW9508 exerts a therapeutic effect to improve hepatic steatosis through a p38-dependent pathway. Thus, investigation of chemicals that act on FFAR1 might be a new strategy for the treatment of hepatic steatosis.

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