ABSTRACT
INTRODUCTION AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) starts with the abnormal accumulation of lipids in the liver. Long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) was reported to modulate hepatic metabolic homeostasis in NAFLD. However, little is known about the molecular mechanisms of NAFLD. MATERIALS AND METHODS: To establish a NAFLD cellular model, HepG2 cells and LO2 cells were treated with 1 mM free fatty acids (FFAs) for 24 h. NEAT1, miRNA (miR)-139-5p, c-Jun and sterol-regulatory element binding protein-1c (SREBP-1c) were evaluated using qPCR. The protein levels of c-Jun, SREBP1c, acetyl-CoA carboxylase (ACC) and fatty acid synthetase (FAS) were determined using western blotting. Moreover, Oil Red O staining was employed to assess lipid accumulation. In addition, a kit assay was performed to evaluate TG levels. Finally, the interactions among NEAT1, miR-139-5p, c-Jun and SREBP1c were identified by dual luciferase reporter gene assay. RESULTS: NEAT1, c-Jun and SREBP1c expression was markedly elevated, while miR-139-5p expression was reduced in the NAFLD cellular model. NEAT1 knockdown restrained lipid accumulation in the NAFLD cellular model by directly targeting miR-139-5p. Moreover, miR-139-5p overexpression suppressed lipid accumulation by directly suppressing c-Jun expression. In addition, c-Jun silencing suppressed lipid accumulation by directly targeting SREBP1c. Finally, miR-139-5p inhibition mitigated the inhibitory effect of sh-NEAT1 on lipid accumulation. CONCLUSION: NEAT1 aggravated FFA-induced lipid accumulation in hepatocytes by regulating the c-Jun/SREBP1c axis by sponging miR-139-5p, indicating the potential of NEAT1 as a promising therapeutic target for NAFLD.
Subject(s)
MicroRNAs , Non-alcoholic Fatty Liver Disease , RNA, Long Noncoding/genetics , Humans , Lipids , MicroRNAs/genetics , MicroRNAs/metabolism , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , RNA, Long Noncoding/metabolism , Sterol Regulatory Element Binding Protein 1/genetics , Sterol Regulatory Element Binding Protein 1/metabolismABSTRACT
As one of the most common liver disorders worldwide, nonalcoholic fatty liver disease (NAFLD) begins with the abnormal accumulation of triglyceride (TG) in the liver and can lead to inflammation and fibrosis. Long noncoding RNA (lncRNA) NEAT1 was reported to promote NAFLD progress. However, its molecular mechanism in NAFLD was not fully clear. In vitro cellular model of NAFLD was established with BRL3A cell treated by free fatty acid (FFA). Cell Counting Kit-8 (CCK-8) assay was carried out to assess cell proliferation. The expression of mRNA and protein of inflammation and fibrosis in BRL3A cell was detected by qRT-PCR and Western blot. Bioinformatics and dual-luciferase reporter assays were used to predict and validate the interaction between NEAT1 and miR-506 as well as GLI3 and miR-506. NEAT1 was upregulated while miR-506 was downregulated in the progression of NAFLD. Meanwhile, NEAT1 and miR-506 were proved to regulate fibrosis, inflammatory response, and lipid metabolism. Knockdown of NEAT1 inhibited GLI3 expression and promoted miR-506 expression, Overexpression of miR-506 inhibited NEAT1 and GLI3 expression. Moreover, dual-luciferase reporter assays proved that miR-506 could bind to NEAT1 and GLI3, whereas NEAT1 could sponge miR-506 to regulate GLI3 expression. lncRNA NEAT1 could regulate fibrosis, inflammatory response, and lipid metabolism via the miR-506/GLI3 axis as a ceRNA, which is a novel mechanistic role in the regulation of NAFLD. These results provide a new potential treatment target for NAFLD.
Subject(s)
Inflammation/genetics , MicroRNAs/genetics , Non-alcoholic Fatty Liver Disease/genetics , Zinc Finger Protein Gli3/genetics , Animals , Cell Line , Cell Proliferation/genetics , Disease Progression , Down-Regulation/genetics , Fibrosis , Gene Expression Regulation, Neoplastic/genetics , Lipid Metabolism/genetics , RNA, Messenger/genetics , Rats , Up-Regulation/geneticsABSTRACT
AIM: To investigate the association of transforming growth factor-beta 1 (TGF-ß1) C-509T polymorphism and susceptibility to cancer by means of meta-analysis. METHODS: An extensive search was performed to identify eligible case-control studies investigating such a link. The strength of the association between TGF-ß1 C-509T polymorphism and cancer risk was assessed by pooled odds ratios (ORs) and 95%confidence intervals (95%CIs) in fixed or random effects models. RESULTS: 55 published case-control studies with a total number of 21,639 cases and 28,460 controls were included. Overall, there was no association between TGF-ß1 C-509T and cancer risk in all genetic comparison models (TT vs. CC: OR=1.01, 95%CI=0.89-1.15; T vs. C: OR=1.01, 95%CI=0.94-1.07). However, a stratified analysis by cancer type indicated -509 T allele was significantly associated with decreased risk of colorectal cancer (CRC) (TT vs. CT/CC: OR=0.85, 95%CI=0.76-0.95), especially for Caucasians (TT vs. CT/CC: OR=0.83, 95%CI=0.71-0.98) and for population-based studies (TT vs. CT/CC: OR=0.78, 95%CI=0.68- 0.89). CONCLUSION: This meta-analysis suggested that TGF-ß1 C-509T polymorphism might contribute to a decreased risk on colorectal cancer susceptibility, especially for Caucasians.
