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

Cai, Yan; Jogasuria, Alvin; Yin, Hu-Quan; Xu, Mingjiang; Hu, Xudong; Wang, Jiayou; Kim, Chun Ki; Wu, Jiashin; Lee, Kwang Won; Gao, Bin; You, Min

doi:10.1016/j.ajpath.2016.05.006

Cited by 45 publications

(66 citation statements)

References 38 publications

(55 reference statements)

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“…Liver Cyp7a1 gene expression was decreased in chronically ethanol-fed mice (36,37). Human alcoholic fatty liver samples also had lower hepatic CYP7A1 mRNA expression levels (37).…”

Section: Discussionmentioning

confidence: 97%

“…Liver Cyp7a1 gene expression was decreased in chronically ethanol-fed mice (36,37). Human alcoholic fatty liver samples also had lower hepatic CYP7A1 mRNA expression levels (37). On the other hand, several lines of evidence demonstrate that ethanol consumption alters bile acid synthesis by up-regulating the expression of bile acid synthesis genes, including Cyp7a1, Cyp8b1, and Cyp27a1 (50 -52).…”

Section: Discussionmentioning

confidence: 99%

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MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis

Jogasuria

Wang

et al. 2016

Journal of Biological Chemistry

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MitoNEET (mNT) (CDGSH iron-sulfur domain-containing protein 1 or CISD1) is an outer mitochondrial membrane protein that donates 2Fe-2S clusters to apo-acceptor proteins. In the present study, using a global mNT knock-out (mNTKO) mouse model, we investigated the in vivo functional role of mNT in the development of alcoholic steatohepatitis. Experimental alcoholic steatohepatitis was achieved by pair feeding wild-type (WT) and mNTKO mice with Lieber-DeCarli ethanol-containing diets for 4 weeks. Strikingly, chronically ethanol-fed mNTKO mice were completely resistant to ethanolinduced steatohepatitis as revealed by dramatically reduced hepatic triglycerides, decreased hepatic cholesterol level, diminished liver inflammatory response, and normalized serum ALT levels. Mechanistic studies demonstrated that ethanol administration to mNTKO mice induced two pivotal endocrine hormones, namely, adipose-derived adiponectin and gut-derived fibroblast growth factor 15 (Fgf15). The elevation in circulating levels of adiponectin and Fgf15 led to normalized hepatic and serum levels of bile acids, limited hepatic accumulation of toxic bile, attenuated inflammation, and amelioration of liver injury in the ethanol-fed mNTKO mice. Other potential mechanisms such as reduced oxidative stress, activated Sirt1 signaling, and diminished NF-B activity also contribute to hepatic improvement in the ethanol-fed mNTKO mice. In conclusion, the present study identified adiponectin and Fgf15 as pivotal adipose-gut-liver metabolic coordinators in mediating the protective action of mNT deficiency against development of alcoholic steatohepatitis in mice. Our findings may help to establish mNT as a novel therapeutic target and pharmacological inhibition of mNT may be beneficial for the prevention and treatment of human alcoholic steatohepatitis.NEET proteins (mitoNEET (CISD1, mNT), 3 nutrient-deprivation autophagy factor-1 (NAF-1; CISD2), and Miner 2 (CISD3)) are a class of redox active iron-sulfur (2Fe-2S) proteins (1, 2). Among the three NEET family members, mNT encoded by the CISD1 gene is the founding member of the NEET family, and it is localized in the outer mitochondrial membrane and regulates the maturation and shuttling of 2Fe-2S clusters. mNT has been identified as a mitochondrial target of the anti-diabetic thiazolidinedione drugs (3, 4). Thiazolidinediones such as pioglitazone are capable of binding and stabilizing the mNT protein against 2Fe-2S cluster release, and thus, protecting tissue from mitochondrial injury (4). NAF-1 encoded by CISD2 is closely related to mNT, sharing 44% overall sequence identity and highly similar structure and functions (1, 5). However, the functions of CISD3 are not well understood.Increasing evidences have revealed that mNT is an important regulator of diverse biological processes, including mitochondrial function, iron metabolism, reactive oxygen species (ROS) homeostasis, lipid metabolism, inflammation process, and autophagy (1-4, 6 -15). Utilizing gain and loss of function mouse models, studies have demo...

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“…Liver Cyp7a1 gene expression was decreased in chronically ethanol-fed mice (36,37). Human alcoholic fatty liver samples also had lower hepatic CYP7A1 mRNA expression levels (37).…”

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis

Jogasuria

Wang

et al. 2016

Journal of Biological Chemistry

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“…22 Meanwhile, Lcn2, a new discovered molecule functioning in the pathogenesis of AFLD, has been shown at an increased level in liver induced by ethanol or adenovirus-miR-217. 6,14,20 Intriguingly, overexpression of Lcn2 mediated by adenovirus in the hepatocytes or mouse liver exacerbated the proceeding of AFLD, which is linked to the inhibition of SIRT1 protein. 6,14 Additionally, ethanol may inhibit SIRT1 activity via interfering in its post-translational modifications, including acetylation, phosphorylation as well as sumoylation.…”

Section: Ethanol Downregulates Hepatic Sirt1mentioning

confidence: 99%

“…6,14,20 Intriguingly, overexpression of Lcn2 mediated by adenovirus in the hepatocytes or mouse liver exacerbated the proceeding of AFLD, which is linked to the inhibition of SIRT1 protein. 6,14 Additionally, ethanol may inhibit SIRT1 activity via interfering in its post-translational modifications, including acetylation, phosphorylation as well as sumoylation. 6 Altogether, ethanol downregulates hepatic SIRT1 in multifarious manners.…”

Section: Ethanol Downregulates Hepatic Sirt1mentioning

confidence: 99%

“…14 In the liver, ethanol oxidizes to acetaldehyde via the catalysis of alcohol dehydrogenase (ADH), microsomal ethanol oxidation system and catalase, then oxidizing to acetic acid by acetaldehyde dehydrogenase 2 (ALDH2). 15 The redox state has been changed in the procedure of ethanol metabolism, which reduces the ratio of NAD þ /NADH as the result of the conversion from NAD þ to NADH.…”

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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Hepatocytes and neutrophils cooperatively suppress bacterial infection by differentially regulating lipocalin‐2 and neutrophil extracellular traps

Feng

Cai

et al. 2018

Hepatology

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

Cited by 45 publications

References 38 publications

MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis

MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis

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

Hepatocytes and neutrophils cooperatively suppress bacterial infection by differentially regulating lipocalin‐2 and neutrophil extracellular traps

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