MicroRNA-217 Promotes Ethanol-induced Fat Accumulation in Hepatocytes by Down-regulating SIRT1

Yin, Hu-Quan; Hu, Ming; Zhang, Ray; Shen, Zheng; Flatow, Laura; You, Min

doi:10.1074/jbc.m111.333534

Cited by 147 publications

(133 citation statements)

References 39 publications

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“…35 We have previously shown that hepatic miR-34a levels were significantly elevated in AML-12 hepatocytes exposed to ethanol or in livers of ethanol-fed mice. 32,36 Ethanol-mediated LCN2 may inhibit Nampt gene and protein expression via directly up-regulating miR34a levels. Intriguingly, similar to Nampt, miR-34a also selectively targets hepatic b-KL but not FGFR4 by binding to the 3 0 UTR of b-KL mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…32 Conversely, miR-217 inhibition by antiemiR-217 or overexpression of SIRT1wt in hepatocytes completely abolished the ability of ethanol to induce LCN2, suggesting a causal role of miR-217-SIRT1 axis in mediating the effect of ethanol on LCN2 ( Figure 6, C and D). Consistent with these in vitro findings, LCN2 protein levels were substantially increased in the serum samples from the previously studied ethanol-fed WT mice, and further significantly augmented in the ethanol-fed liver-specific deletion of Sirt1 (Sirt1LKO) mice (Supplemental Figure S6).…”

Section: Ethanol-mediated Perturbation Of Mir-217-sirt1 Axis Induces mentioning

confidence: 94%

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The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice

Cai

Jogasuria

Yin

et al. 2016

The American Journal of Pathology

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We have previously shown that the ethanol-mediated elevation of lipocaline-2 (LCN2) is closely associated with the development of alcoholic fatty liver disease (AFLD) in mice. Herein, we aimed to understand the functional significance of LCN2 induction by ethanol and to explore its underlying mechanisms. We evaluated the effects of LCN2 in an in vitro cellular alcoholic steatosis model and in an animal study using wild-type and LCN2 knockout mice fed for 4 weeks with an ethanol-supplemented Lieber-DeCarli diet. In the cellular model of alcoholic steatosis, recombinant LCN2 or overexpression of LCN2 exacerbated ethanol-induced fat accumulation, whereas knocking down LCN2 prevented steatosis in hepatocytes exposed to ethanol. Consistently, removal of LCN2 partially but significantly alleviated alcoholic fatty liver injury in mice. Mechanistically, LCN2 mediates detrimental effects of ethanol in the liver via disrupted multiple signaling pathways, including aberrant nicotinamide phosphoribosyltransferaseesirtuin 1 axis, perturbed endocrine metabolic regulatory fibroblast growth factor 15/19 signaling, and impaired chaperone-mediated autophagy. Finally, compared with healthy human livers, liver samples from patients with AFLD had lower gene expression of several LCN2-regualted molecules. Our study demonstrated a pivotal and causal role of LCN2 in the development of AFLD and suggested that targeting the LCN2 could be of great value for the treatment of human AFLD. (Am J Pathol 2016 http://dx

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Section: Discussionmentioning

confidence: 99%

Section: Ethanol-mediated Perturbation Of Mir-217-sirt1 Axis Induces mentioning

confidence: 94%

The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice

Cai

Jogasuria

Yin

et al. 2016

The American Journal of Pathology

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“…The mechanisms that contribute to development of HCC in patients with cirrhosis are complex and include telomere shortening, activation of pathways that promote tumor cell survival, proliferation, loss of cell cycle checkpoints, and activation of oncogenes [185,186] . In addition, the immunosuppressive effects of alcohol [185,186] contribute to the development of HCC in patients with ALD [187][188][189] . Recently, interesting data about epigenetic regulation in ALD have been published.…”

Section: Alcohol and Hepatocarcinogenesismentioning

confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

413

339

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Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility. Key words: Alcohol metabolism; Acetaldehyde; Reactive oxygen species; Alcoholic liver disease; Protein adducts; Hepatic stellate cells; Liver fibrosis; CYP2E1Core tip: The goal of this article is to review the mechanisms of alcohol-mediated toxicity in parenchymal and non-parenchymal cells of the liver. Specifically, we highlight the effect of oxidative ethanol metabolites such as acetaldehyde and reactive oxygen species in the development of fat accumulation, fibrosis and deranged immune response.Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism.

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“…20 In cultured mouse AML-12 hepatocytes and in the livers of chronically ethanol-fed mice, miR-217 (an endogenous inhibitor of SIRT1) is upregulated to impair SIRT1, via binding to the 3 0 UTR of SIRT1 mRNAs and causing mRNA cleavage or suppressing its translation. 12 Besides, it has also been confirmed that both miR-217 overexpression and alcohol consumption inhibit SIRT1 deacetylase activity in AML-12 cells. 12 Utilizing primary kupffer cells (KCs) or cultured RAW 264.7 macrophages, Yin et al had demonstrated that ethanol obviously increased miR-217 abundance and notably magnified LPS-induced miR-217 expression.…”

Section: Ethanol Downregulates Hepatic Sirt1mentioning

confidence: 90%

Roles of silent information regulator 1–serine/arginine-rich splicing factor 10–lipin 1 axis in the pathogenesis of alcohol fatty liver disease

Zhou

2017

Exp Biol Med (Maywood)

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Impact statementALD is a major health burden in industrialized countries as well as China. AFLD, the earliest and reversible form of ALD, can progress to hepatitis, fibrosis/cirrhosis, even hepatoma. While the mechanisms, by which ethanol consumption leads to AFLD, are complicated and multiple, and remain incompletely understood. SIRT1, SFRS10, and LIPIN1 had been separately reported to participate in lipid metabolism and the pathogenesis of AFLD. Noteworthy, we found the connection among them via searching articles in PubMed and we had elaborated the connection in detail in this minireview. It seems a new signaling axis, SIRT1-SFRS10-LIPIN1 axis, acting in the pathogenesis of AFLD exists. Further study aimed at SIRT1-SFRS10-LIPIN1 signaling system will possibly offer a more effective therapeutic target for AFLD. AbstractAlcohol exposure is a major reason of morbidity and mortality all over the world, with much of detrimental consequences attributing to alcoholic liver disease (ALD). With the continued ethanol consumption, alcoholic fatty liver disease (AFLD, the earliest and reversible form of ALD) can further develop to more serious forms of alcoholic liver damage, including alcoholic steatohepatitis, fibrosis/cirrhosis, and even eventually progress to hepatocellular carcinoma and liver failure. Furthermore, cell trauma, inflammation, oxidative stress, regeneration, and bacterial translocation are crucial promoters of ethanol-mediated liver lesions. AFLD is characterized by excessive fat deposition in liver induced by excessive drinking, which is related closely to the raised synthesis of fatty acids and triglyceride, reduction of mitochondrial fatty acid b-oxidation, and the aggregation of very-low-density lipoprotein (VLDL). Although little is known about the cellular and molecular mechanisms of AFLD, it seems to be correlated to diverse signal channels. Massive studies have suggested that liver steatosis is closely associated with the inhibition of silent information regulator 1 (SIRT1) and the augment of lipin1 b/a ratio mediated by ethanol. Recently, serine/argininerich splicing factor 10 (SFRS10), a specific molecule functioning in alternative splicing of lipin 1 (LPIN1) pre-mRNAs, has emerged as the central connection between SIRT1 and lipin1 signaling. It seems a new signaling axis, SIRT1-SFRS10-LPIN1 axis, acting in the pathogenesis of AFLD exists. This article aims to further explore the interactions among the above three molecules and their influences on the development of AFLD.

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MicroRNA-217 Promotes Ethanol-induced Fat Accumulation in Hepatocytes by Down-regulating SIRT1

Cited by 147 publications

References 39 publications

The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice

The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Roles of silent information regulator 1–serine/arginine-rich splicing factor 10–lipin 1 axis in the pathogenesis of alcohol fatty liver disease

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