miR-217 Regulates Ethanol-Induced Hepatic Inflammation by Disrupting Sirtuin 1–Lipin-1 Signaling

Yin, Hu-Quan; Liang, Xiaomei; Jogasuria, Alvin; Davidson, Nicholas O.; You, Min

doi:10.1016/j.ajpath.2015.01.030

Cited by 56 publications

(50 citation statements)

References 37 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%

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%

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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“…Sirt-1 reduction by up-regulated miRNA (miR-181) also occurs in the hippocampus of a mouse AD model (3×Tg) [170]. Sirtuin regulation by microRNAs might be in fact a widespread phenomenon in inflammatory and thus possibly neurodegenerative conditions: links exist between miRNA-34a, -132, -138, -217, -373-and -520c-mediated Sirt1 reduction with NF-κB signalling (at least in the periphery) [49,115,191,220,231], and a reciprocal impact of NF-κB on Sirt1 expression via miRNA has been noted [94]. Some of the Sirt1-regulating miRNAs also respond to oxidative stress, further supporting their potential involvement in neurodegenerative insults [34].…”

Section: A B Cmentioning

confidence: 99%

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

Jęśko¹,

Strosznajder²

2016

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A b s t r a c tSirtuins vast number of targets in many cellular compartments, and some display additional enzymatic activities including mono(ADP-ribosyl)ation. SIRTs interact with multiple signalling proteins, transcription factors and enzymes including p53, FOXOs (forkhead box subgroup O), PPARs (peroxisome proliferator-activated receptors), NF-κB, and DNA-PK (DNA-dependent protein kinase). Sirtuins also interact extensively with the family of poly(ADPribose) polymerases (PARPs), a crucial and widespread class of NAD

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“…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. 20 Simultaneously, the study showed that SIRT1 mRNA and protein, human transformer-2-beta gene mRNA and lipin1a mRNA expression were both markedly lessened, whereas total lipin1 and lipin1b mRNA were Figure 1 Ethanol downregulates SIRT1 and SFRS10 protein levels by phosphorylation of HuR. Ethanol induces phosphorylation of HuR via oxidative stress, and then impairs SIRT1 and SFRS10 expression enhanced in the livers of mice injected with adenovirusmiR-217 compared with controls.…”

Section: Ethanol Downregulates Hepatic Sirt1mentioning

confidence: 99%

“…Ethanol induces phosphorylation of HuR via oxidative stress, and then impairs SIRT1 and SFRS10 expression enhanced in the livers of mice injected with adenovirusmiR-217 compared with controls. 20 Taken together, ethanol administration might worsen steatosis and inflammation in hepatocytes, via disruption of miR-217-SIRT1-SFRS10-lipin1 axis. 20 HuR and miR-217 may exert synergistic effects in signal channels of SIRT1 impairment, although no direct proofs confirm that ethanol increases the number of phosphorylated HuR degrading SIRT1 mRNA.…”

Section: Ethanol Downregulates Hepatic Sirt1mentioning

confidence: 99%

“…5 LPS, acetaldehyde, and acetate have been confirmed to promote the production of ROS in cultured hepatic cells, 5 subsequently inhibiting SIRT1 activity and disrupting SIRT1 signaling. 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.…”

Section: Ethanol Downregulates Hepatic Sirt1mentioning

confidence: 99%

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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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miR-217 Regulates Ethanol-Induced Hepatic Inflammation by Disrupting Sirtuin 1–Lipin-1 Signaling

Cited by 56 publications

References 37 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

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

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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