ATF4 overexpression induces early onset of hyperlipidaemia and hepatic steatosis and enhances adipogenesis in zebrafish

Yeh, Kun Yun; Lai, Chien-Yu; Lin, Chiu Ya; Hsu, Chia-Chen; Lo, Chung Ping; Her, Guor Mour

doi:10.1038/s41598-017-16587-9

Cited by 47 publications

(33 citation statements)

References 55 publications

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“…Levels of free cholesterol and triglycerides (TG) in the liver were determined by colorimetric and enzymatic assays following the manufacturers’ protocols (Sigma-Aldrich, St. Louis, MO, USA). Biochemical analyses of zebrafish liver lipids were performed, as previously described [ 32 , 58 ]. Hepatic MDA and H 2 O 2 levels were determined using commercial kits (Wako, Chuo-ku, and Osaka, Japan).…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-27b Depletion Enhances Endotrophic and Intravascular Lipid Accumulation and Induces Adipocyte Hyperplasia in Zebrafish

Hsu

Lai

Lin

et al. 2017

IJMS

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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.

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Section: Methodsmentioning

confidence: 99%

MicroRNA-27b Depletion Enhances Endotrophic and Intravascular Lipid Accumulation and Induces Adipocyte Hyperplasia in Zebrafish

Hsu

Lai

Lin

et al. 2017

IJMS

Self Cite

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“…Enhanced ATF4 expression causes increases in lipogenic gene and protein expression and triglyceride level in primary hepatocytes [47]. Similarly, transgenic overexpression of ATF4 results in increased lipid accumulation, leading to hepatic steatosis in zebrafish [58]. Given that FTO is a positive regulator of ATF4 expression, increased activity of the hepatic FTO-ATF4 system may promote hepatic lipid accumulation, while inhibition of this system may contribute to the reduced lipid deposition in liver (Figure 3).…”

Section: G6pase Pckmentioning

confidence: 99%

Fat Mass and Obesity Associated (FTO) Gene and Hepatic Glucose and Lipid Metabolism

Mizuno

2018

Preprint

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Common genetic variants of the fat mass and obesity associated (FTO) gene are strongly associated with obesity and type 2 diabetes. FTO is ubiquitously expressed, but appears to have tissue-specific roles. Earlier studies have focused on the role of hypothlamic FTO in the regulation of metabolism. However, it appears that FTO plays a role in the regulation of metabolism in a tissue-specific manner. Recent studies suggest that expression of hepatic FTO is regulated by metabolic signals such as nutrients and hormones and altered FTO levels in liver affects glucose and lipid metabolism. This review outlines recent findings on hepatic FTO in the regulation of metabolism, with particular focus on hepatic glucose and lipid metabolism. It is proposed that abnormal activity of hepatic signaling pathways involving FTO links metabolic impairments such as obesity, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). Therefore, a better understanding of these pathways may lead to therapeutic approaches to treat these metabolic diseases by targeting hepatic FTO. The overall goal of this review is to place FTO within the context of hepatic regulation of metabolism.

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“…Over the last decade, the zebrafish ( Danio rerio ) has been increasingly employed in investigating human obesity and obesity-related diseases, including visceral adiposity [ 17 , 18 ], hepatic steatosis [ 19 ], atherosclerosis [ 20 , 21 ], and type 2 diabetes [ 22 ]. Overfed diet-induced obesity (DIO) zebrafish exhibit increased body weight gain, hypertriglyceridemia, hepatic steatosis [ 23 , 24 ], and visceral adiposity [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Anti-Obesity Properties of Palmaria mollis in Zebrafish and Mouse Models

et al. 2018

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(1) Background: The red seaweed Palmaria mollis (PM), which has a bacon-like taste, is increasingly being included in Western diets. In this study, we evaluate anti-obesity effects of PM using diet-induced obese (DIO) zebrafish and mice models. (2) Methods: We fed PM-containing feed to DIO-zebrafish and mice, and evaluated the anti-obesity effects We also analyzed gene expression changes in their liver and visceral adipose tissues (VAT). (3) Results: PM ameliorated several anti-obesity traits in both animals, including dyslipidaemia, hepatic steatosis, and visceral adiposity. In liver tissues of DIO-zebrafish and mice, PM upregulated gene expressions involved in peroxisome proliferator-activated receptor alpha (PPARA) pathways, and downregulated peroxisome proliferator-activated receptor gamma (PPARG) pathways, suggesting that the lipid-lowering effect of PM might be caused by activation of beta-oxidation and inhibition of lipogenesis. In VAT, PM downregulated genes involved in early and late adipocyte differentiation in zebrafish, but not in mice. (4) Conclusions: We have demonstrated that PM can prevent hepatic steatosis and visceral adiposity for the first time. Dietary supplementation of PM as a functional food may be suitable for obesity prevention and reduction in the prevalence of obesity-related diseases.

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ATF4 overexpression induces early onset of hyperlipidaemia and hepatic steatosis and enhances adipogenesis in zebrafish

Cited by 47 publications

References 55 publications

MicroRNA-27b Depletion Enhances Endotrophic and Intravascular Lipid Accumulation and Induces Adipocyte Hyperplasia in Zebrafish

MicroRNA-27b Depletion Enhances Endotrophic and Intravascular Lipid Accumulation and Induces Adipocyte Hyperplasia in Zebrafish

Fat Mass and Obesity Associated (FTO) Gene and Hepatic Glucose and Lipid Metabolism

Novel Anti-Obesity Properties of Palmaria mollis in Zebrafish and Mouse Models

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