title: Effects of the new thiazolidine derivative LPSF/GQ-02 on hepatic lipid metabolism pathways in non-alcoholic fatty liver disease (NAFLD).
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.affiliation: Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil. Electronic address: shyrlenemra@gmail.com.
authors.forename: Shyrlene
authors.initials: S
authors.lastname: Araújo
authors.affiliation: Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.
authors.forename: Amanda
authors.initials: A
authors.lastname: Soares E Silva
authors.affiliation: Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Gomes
authors.affiliation: Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.
authors.forename: Edlene
authors.initials: E
authors.lastname: Ribeiro
authors.affiliation: Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.
authors.forename: Wilma
authors.initials: W
authors.lastname: Oliveira
authors.affiliation: Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.
authors.forename: Amanda
authors.initials: A
authors.lastname: Oliveira
authors.affiliation: Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil; Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lima
authors.affiliation: Laboratório de Planejamento e Síntese de Fármacos, Universidade Federal de Pernambuco, Recife, Brasil.
authors.forename: Maria do Carmo
authors.initials: MDC
authors.lastname: Lima
authors.affiliation: Laboratório de Planejamento e Síntese de Fármacos, Universidade Federal de Pernambuco, Recife, Brasil.
authors.forename: Ivan
authors.initials: I
authors.lastname: Pitta
authors.affiliation: Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães (FIOCRUZ), Recife, Pernambuco, Brasil. Electronic address: peixoto.christina@Gmail.com.
authors.forename: Christina
authors.initials: C
authors.lastname: Peixoto
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D064429:Fatty Acid Synthases / Q000378:metabolism; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008049:Lipase / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008066:Lipolysis / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000217:Acyltransferases
chemical_list: D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D064429:Fatty Acid Synthases; D000071161:Forkhead Box Protein O1; D008049:Lipase; D047493:PPAR alpha; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones; C581247:5-(4-chlorobenzylidene)-3-(4-methylbenzyl)thiazolidine-2,4-dione; C497388:Srebf1 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: AMPK and SREBP-1c; LPSF/GQ-02; NAFLD; PPARα; Thiazolidinediones