Cidea promotes hepatic steatosis by sensing dietary fatty acids

Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
Hepatology (Impact Factor: 11.06). 07/2012; 56(1):95-107. DOI: 10.1002/hep.25611
Source: PubMed


High levels of dietary saturated fat have been closely associated with the development of hepatic steatosis, but the factors that mediate this process remain elusive. Here, we observed that the level of cell death-inducing DNA fragmentation factor-alpha-like effector a (Cidea) expression was highly correlated with the severity of hepatic steatosis in humans. Overexpression of Cidea in mouse liver resulted in increased hepatic lipid accumulation and the formation of large lipid droplets (LDs). In contrast, mice with a Cidea deficiency had decreased lipid accumulation and alleviated hepatic steatosis when they received a high-fat-diet feeding or in ob/ob mice. Furthermore, the knockdown of Cidea in livers of ob/ob mice resulted in significantly reduced hepatic lipid accumulation and smaller LDs. Importantly, we observed that Cidea expression in hepatocytes was specifically induced by saturated fatty acids (FAs), and such induction was reduced when sterol response element-binding protein (SREBP)1c was knocked down. In contrast, the overexpression of SREBP1c restored the saturated FA-induced expression of Cidea. In addition, we observed that the stability of Cidea protein in hepatocytes increased significantly in response to treatment with FAs. CONCLUSION: Cidea plays critical roles in promoting hepatic lipid accumulation and in the development of hepatic steatosis by acting as a sensor that responds to diets that contain FAs.

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    • "To examine NAFLD development in the INT-fed animals at a molecular level in more detail, we analyzed the expression of genes involved in lipid droplet formation, which are known to be highly correlated with the severity of NAFLD [30] [31] [32]. Q-PCR analysis was performed on all mice of all four intervention groups for cell death-inducing DFFA-like effector A (Cidea) and C (Cidec), monoacylglycerol O-acyltransferase 1 (Mogat1), and fibroblast growth factor 21 (Fgf21; Fig. 3B). "
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    ABSTRACT: ScopeWe investigated whether a novel dietary intervention consisting of an every-other-week calorie-restricted diet could prevent nonalcoholic fatty liver disease (NAFLD) development induced by a medium-fat (MF) diet.Methods and resultsNine-week-old male C57BL/6J mice received either a (i) control (C), (ii) 30E% calorie restricted (CR), (iii) MF (25E% fat), or (iv) intermittent (INT) diet, a diet alternating weekly between 40E% CR and an ad libitum MF diet until sacrifice at the age of 12 months. The metabolic, morphological, and molecular features of NAFLD were examined. The INT diet resulted in healthy metabolic and morphological features as displayed by the continuous CR diet: glucose tolerant, low hepatic triglyceride content, low plasma alanine aminotransferase. In contrast, the C- and MF-exposed mice with high body weight developed signs of NAFLD. However, the gene expression profiles of INT-exposed mice differed to those of CR-exposed mice and showed to be more similar with those of C- and MF-exposed mice with a comparable body weight.Conclusions Our study reveals that the INT diet maintains metabolic health and reverses the adverse effects of the MF diet, thus effectively prevents the development of NAFLD in 12-month-old male C57BL/6J mice.
    Molecular Nutrition & Food Research 12/2014; 59(3). DOI:10.1002/mnfr.201400621 · 4.60 Impact Factor
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    • "Increased hepatic mRNA expression of Cidea and Cidec was present in WW offspring indicative of abnormal elevation of lipid droplet formation. Cidea mRNA expression has been shown to be highly correlated with the development of hepatic steatosis in humans (Zhou et al. 2012). CIDEC also mediated the development of hepatic steatosis (Matsusue et al. 2008 "
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    ABSTRACT: Metabolic programming via components of the maternal diet during gestation may play a role in the development of different aspects of the metabolic syndrome. Using a mouse model we aimed to characterize the role of maternal western type diet in the development of non-alcoholic fatty liver disease (NAFLD) in the offspring. Female mice were fed either a western (W) or low-fat control (L) semi-synthetic diet before and during gestation and lactation. At weaning, male offspring were assigned either the W or the L diet, generating four experimental groups: WW, WL, LW and LL offspring. Biochemical, histological and epigenetic indicators were investigated at 29 weeks of age. Male offspring exposed to prenatal and post-weaning western-style diet (WW) showed hepatomegaly combined with accumulation of hepatic cholesterol and triglycerides. This accumulation was associated with up-regulation of de novo lipid synthesis, inflammation and dysregulation of lipid storage. Elevated hepatic transaminases and increased expression of Tnfa, Cd11, Mcp1 and Tgfb underpin the severity of liver injury. Histopathological analysis revealed the presence of advanced steatohepatitis in WW offspring. In addition, alterations in DNA methylation in key metabolic genes (Ppara, Insig, and Fasn) were detected. Maternal dietary fat intake during early development programs susceptibility to liver disease in male offspring, mediated by disturbances in lipid metabolism and inflammatory response. Long lasting epigenetic changes may underlie this dysregulation. This article is protected by copyright. All rights reserved.
    Acta Physiologica 11/2013; 210(1). DOI:10.1111/apha.12197 · 4.38 Impact Factor
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    • "All members of the CIDE family have functional roles in LD clustering and fusion [9] [10] [11] [12] [13]. Interestingly, CIDEB is the only member of the family that is constitutively expressed in the liver and implicated in VLDL maturation [11] [14]. Aside from primary cell culture and mice models, there are limited models to study CIDEB in the liver. "
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    ABSTRACT: Human hepatocytes constitutively express the lipid droplet (LD) associated protein cell death-inducing DFFA-like effector B (CIDEB). CIDEB mediates LD fusion, as well as very-low-density lipoprotein (VLDL) maturation. However, there are limited cell culture models readily available to study CIDEB's role in these biological processes, as hepatoma cell lines express negligible levels of CIDEB. Recent work has highlighted the ability of human serum to differentiate hepatoma cells. Herein, we demonstrate that culturing Huh7.5 cells in media supplemented with human serum activates CIDEB expression. This activation occurs through the induced expression of PGC-1α, a positive transcriptional regulator of CIDEB. Coherent anti-Stokes Raman scattering (CARS) microscopy revealed a correlation between CIDEB levels and LD size in human serum treated Huh7.5 cells. Human serum treatment also resulted in a rapid decrease in the levels of adipose differentiation-related protein (ADRP). Furthermore, individual overexpression of CIDEB was sufficient to down-regulate ADRP protein levels. siRNA knockdown of CIDEB revealed that the human serum mediated increase in LD size was CIDEB-dependent. Overall, our work highlights CIDEB's role in LD fusion, and presents a new model system to study the PGC-1α/CIDEB pathway's role in LD dynamics and the VLDL pathway.
    Biochemical and Biophysical Research Communications 10/2013; 441(2). DOI:10.1016/j.bbrc.2013.10.080 · 2.30 Impact Factor
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