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Effects of the new thiazolidine derivative LPSF/GQ-02 on hepatic lipid metabolism pathways in non-alcoholic fatty liver disease (NAFLD).
Eur J Pharmacol 2016; 788:306-314EJ

Abstract

Non-alcoholic fatty liver disease (NAFLD) is considered the most common manifestation of metabolic syndrome. One of its most important features is the accumulation of triglycerides in the hepatocyte cells. Thiazolidinediones (TZDs) act as insulin sensitizers and are used to treat patients with type 2 diabetes and other conditions that are resistant to insulin, such as hepatic steatosis. Controversially, TZDs are also associated with the development of cardiovascular events and liver problems. For this reason, new therapeutic strategies are necessary to improve liver function in patients with chronic liver diseases. The aim of the present study was to evaluate the effects of LPSF/GQ-02 on the liver lipid metabolism in a murine model of NAFLD. Eighty male LDLR-/- mice were divided into 3 groups: 1-fed with a high-fat diet (HFD); 2-HFD+Pioglitazone (20mg/kg/day); 3-HFD+LPSF/GQ-02 (30mg/kg/day). The experiments lasted 12 weeks and drugs were administered daily by gavage in the final four weeks. The liver was processed for optical microscopy, Oil Red O, immunohistochemistry, immunofluorescence and western blot analysis. LPSF/GQ-02 effectively decreased fat accumulation, increased the hepatic levels of p-AMPK, FoxO1, ATGL, p-ACC and PPARα, and reduced the expression of LXRα, SREBP-1c and ACC. These results suggest that LPSF/GQ-02 acts directly on the hepatic lipid metabolism through the activation of the PPAR-α/AMPK/FoxO1/ATGL lipolytic pathway, and the inhibition of the AMPK/LXR/SREBP-1c/ACC/FAS lipogenic pathway.

Authors+Show Affiliations

Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil. Electronic address: shyrlenemra@gmail.com.Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.Laboratório de Planejamento e Síntese de Fármacos, Universidade Federal de Pernambuco, Recife, Brasil.Laboratório de Planejamento e Síntese de Fármacos, Universidade Federal de Pernambuco, Recife, Brasil.Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil. Electronic address: peixoto.christina@Gmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27349145

Citation

Araújo, Shyrlene, et al. "Effects of the New Thiazolidine Derivative LPSF/GQ-02 On Hepatic Lipid Metabolism Pathways in Non-alcoholic Fatty Liver Disease (NAFLD)." European Journal of Pharmacology, vol. 788, 2016, pp. 306-314.
Araújo S, Soares E Silva A, Gomes F, et al. Effects of the new thiazolidine derivative LPSF/GQ-02 on hepatic lipid metabolism pathways in non-alcoholic fatty liver disease (NAFLD). Eur J Pharmacol. 2016;788:306-314.
Araújo, S., Soares E Silva, A., Gomes, F., Ribeiro, E., Oliveira, W., Oliveira, A., ... Peixoto, C. (2016). Effects of the new thiazolidine derivative LPSF/GQ-02 on hepatic lipid metabolism pathways in non-alcoholic fatty liver disease (NAFLD). European Journal of Pharmacology, 788, pp. 306-314. doi:10.1016/j.ejphar.2016.06.043.
Araújo S, et al. Effects of the New Thiazolidine Derivative LPSF/GQ-02 On Hepatic Lipid Metabolism Pathways in Non-alcoholic Fatty Liver Disease (NAFLD). Eur J Pharmacol. 2016 Oct 5;788:306-314. PubMed PMID: 27349145.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of the new thiazolidine derivative LPSF/GQ-02 on hepatic lipid metabolism pathways in non-alcoholic fatty liver disease (NAFLD). AU - Araújo,Shyrlene, AU - Soares E Silva,Amanda, AU - Gomes,Fabiana, AU - Ribeiro,Edlene, AU - Oliveira,Wilma, AU - Oliveira,Amanda, AU - Lima,Ingrid, AU - Lima,Maria do Carmo, AU - Pitta,Ivan, AU - Peixoto,Christina, Y1 - 2016/06/24/ PY - 2016/04/22/received PY - 2016/06/22/revised PY - 2016/06/23/accepted PY - 2016/6/29/entrez PY - 2016/6/29/pubmed PY - 2017/3/11/medline KW - AMPK and SREBP-1c KW - LPSF/GQ-02 KW - NAFLD KW - PPARα KW - Thiazolidinediones SP - 306 EP - 314 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 788 N2 - Non-alcoholic fatty liver disease (NAFLD) is considered the most common manifestation of metabolic syndrome. One of its most important features is the accumulation of triglycerides in the hepatocyte cells. Thiazolidinediones (TZDs) act as insulin sensitizers and are used to treat patients with type 2 diabetes and other conditions that are resistant to insulin, such as hepatic steatosis. Controversially, TZDs are also associated with the development of cardiovascular events and liver problems. For this reason, new therapeutic strategies are necessary to improve liver function in patients with chronic liver diseases. The aim of the present study was to evaluate the effects of LPSF/GQ-02 on the liver lipid metabolism in a murine model of NAFLD. Eighty male LDLR-/- mice were divided into 3 groups: 1-fed with a high-fat diet (HFD); 2-HFD+Pioglitazone (20mg/kg/day); 3-HFD+LPSF/GQ-02 (30mg/kg/day). The experiments lasted 12 weeks and drugs were administered daily by gavage in the final four weeks. The liver was processed for optical microscopy, Oil Red O, immunohistochemistry, immunofluorescence and western blot analysis. LPSF/GQ-02 effectively decreased fat accumulation, increased the hepatic levels of p-AMPK, FoxO1, ATGL, p-ACC and PPARα, and reduced the expression of LXRα, SREBP-1c and ACC. These results suggest that LPSF/GQ-02 acts directly on the hepatic lipid metabolism through the activation of the PPAR-α/AMPK/FoxO1/ATGL lipolytic pathway, and the inhibition of the AMPK/LXR/SREBP-1c/ACC/FAS lipogenic pathway. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/27349145/Effects_of_the_new_thiazolidine_derivative_LPSF/GQ_02_on_hepatic_lipid_metabolism_pathways_in_non_alcoholic_fatty_liver_disease__NAFLD__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(16)30402-2 DB - PRIME DP - Unbound Medicine ER -