Abstract
miR-27b has emerged as a regulatory hub in cholesterol and lipid metabolism, and as a potential therapeutic target for treating atherosclerosis and obesity. However, the impact of miR-27b on lipid levels in vivo remains to be determined. Zebrafish lipids are normally stored as triacylglycerols (TGs) and their main storage sites are visceral, intramuscular, and subcutaneous lipid depots, and not blood vessels and liver. In this study, we applied microRNA-sponge (miR-SP) technology and generated zebrafish expressing transgenic miR-27b-SP (C27bSPs), which disrupted endogenous miR-27b activity and induced intravascular lipid accumulation (hyperlipidemia) and the early onset of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Oil Red O staining predominantly increased in the blood vessels and livers of larvae and juvenile C27bSPs, indicating that miR-27b depletion functionally promoted lipid accumulation. C27bSPs also showed an increased weight gain with larger fat pads, resulting from adipocyte hyperplasia. Molecular analysis revealed that miR-27b depletion increased the expression of genes that are associated with lipogenesis and the endoplasmic reticulum (ER). Moreover, miR-27b-SP increased peroxisome proliferator-activated receptor γ (PPAR-γ), CCAAT enhancer binding protein-α (C/EBP-α, and sterol regulatory element binding transcription factor 1c (SREBP-1c) expression and contributed to lipogenesis and adipogenesis. Conclusion: Our results suggest that miR-27b-SP acts as a lipid enhancer by directly increasing the expression of several lipogenic/adipogenic transcriptional factors, resulting in increased lipogenesis and adipogenesis. In this study, miR-27b expression improved lipid metabolism in C27bSPs, which suggests that miR-27b is an important lipogenic factor in regulating early onset of hyperlipidemia and adipogenesis in zebrafish.
Highlights
Apart from the classical transcriptional regulators, microRNAs have been shown to participate in almost every metabolic homeostasis process, including adipogenesis [1,2], lipogenesis [3], and glucose-stimulated insulin secretion [4,5], in order to exert influence on metabolic pathways which are involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) [6]
We report the association of Yin Yang 1 (YY1) with hepatic lipid accumulation by down-regulating C/EBP homologous protein 10 (CHOP-10) which repressed the expression of peroxisome proliferator activated receptor-γ (PPAR-γ) and CCAAT enhancer binding protein-α (C/EBP-α) in the lipogenic program in zebrafish larvae and adults [31]
We discovered that oxidative stress significantly increased the quantity of hepatic MDA and the release of H2O2 in hC27bSPs and bC27bSPs; no or less effect of oxidative stress was observed in the liver of WT that was fed with the low-fat diet (LFD) (Figure 5D), suggesting that miR-27b depletion can significantly enhance oxidative stress in zebrafish livers
Summary
Apart from the classical transcriptional regulators, microRNAs (miRs) have been shown to participate in almost every metabolic homeostasis process, including adipogenesis [1,2], lipogenesis [3], and glucose-stimulated insulin secretion [4,5], in order to exert influence on metabolic pathways which are involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) [6]. Vickers et al, provided in silico, in vitro and in vivo evidence that miR-27b is a strong candidate to be a regulatory hub in lipid metabolism [22] They demonstrated that hepatic miR-27b is responsive to lipid levels and regulates the expression (mRNA and protein) of key metabolic genes, including angiopoietin-like 3 (ANGPTL3) and glycerol-3-phosphate acyltransferase 1 (GPAM), which have been previously implicated in the pathobiology of lipid-related disorders [22]. Despite these observations, to date, no reports are available regarding the impact of miR-27b on lipid metabolism in vivo
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