Lipocalin‐2 (NGAL/LCN2), a “help‐me” signal in organ inflammation

Asimakopoulou, Anastasia; Borkham-Kamphorst, Erawan; Tacke, Frank; Weiskirchen, Ralf

doi:10.1002/hep.27930

Cited by 38 publications

(43 citation statements)

References 6 publications

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“…In line with recent reports, we observed significantly increased liver Lcn2 expression in the context of obesity and hepatic steatosis (Auguet et al, 2013; Ye et al, 2014; Asimakopoulou et al, 2016). More specifically, the reduction of RNA expression of inflammatory markers associated with increased Lcn2 expression suggests some regulatory hepatic mechanism in response to 10 weeks of HFHF consumption (Alwahsh et al, 2014; Asimakopoulou et al, 2014).…”

Section: Discussionsupporting

confidence: 93%

Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice

Rodrigues

Bekhbat

Houser

et al. 2017

Brain, Behavior, and Immunity

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The mechanisms underlying the association between chronic psychological stress, development of metabolic syndrome (MetS), and behavioral impairment in obesity are poorly understood. The aim of the present study was to assess the effects of mild chronic psychological stress on metabolic, inflammatory, and behavioral profiles in a mouse model of diet-induced obesity. We hypothesized that (1) high-fat high-fructose diet (HFHF) and psychological stress would synergize to mediate the impact of inflammation on the central nervous system in the presence of behavioral dysfunction, and that (2) HFHF and stress interactions would impact insulin and lipid metabolism. C57Bl/6 male mice underwent a combination of HFHF and two weeks of chronic psychological stress. MetS-related conditions were assessed using untargeted plasma metabolomics, and structural and immune changes in the gut and liver were evaluated. Inflammation was measured in plasma, liver, gut, and brain. Our results show a complex interplay of diet and stress on gut alterations, energetic homeostasis, lipid metabolism, and plasma insulin levels. Psychological stress and HFHF diet promoted changes in intestinal tight junctions proteins and increases in insulin resistance and plasma cholesterol, and impacted the RNA expression of inflammatory factors in the hippocampus. Stress promoted an adaptive anti-inflammatory profile in the hippocampus that was abolished by diet treatment. HFHF increased hippocampal and hepatic Lcn2 mRNA expression as well as LCN2 plasma levels. Behavioral changes were associated with HFHF and stress. Collectively, these results suggest that diet and stress as pervasive factors exacerbate MetS-related conditions through an inflammatory mechanism that ultimately can impact behavior. This rodent model may prove useful for identification of possible biomarkers and therapeutic targets to treat metabolic syndrome and mood disorders.

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Section: Discussionsupporting

confidence: 93%

Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice

Rodrigues

Bekhbat

Houser

et al. 2017

Brain, Behavior, and Immunity

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“…4 Paradoxically, mNT deficiency increased circulating Lcn2 in ethanol-fed mice. Emerging evidences suggest that Lcn2 also exerts protective functions against liver injuries by acting as a "help me" signal (54). It is tempting to speculate that mNT deficiency-mediated elevation of Lcn2 may trigger antiinflammatory signaling and protect the mice from ethanol-induced liver damage.…”

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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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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“…Notably, LCN2 was shown to be upregulated in response to cellular stress and to play an important role in promoting protective effects in a liver injury model. Others have suggested that LCN2 might act as an intrinsic "help me" sensor that recruits inflammatory cells to damaged tissue [27] .…”

Section: Discussionmentioning

confidence: 99%

Altered Systemic Adipokines in Patients with Chronic Urticaria

Trinh¹,

Pham²,

Ban³

et al. 2016

Int Arch Allergy Immunol

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Background: Increasing evidence suggests that adipokines affect immune responses and chronic urticaria (CU) is associated with an altered immune response related to chronic systemic inflammation. Our objectives were to investigate whether adipokines are involved in CU pathogenesis and to outline relationships between adipokines and urticaria severity and quality of life. Methods: Serum adiponectin, leptin, lipocalin-2 (LCN2), interleukin (IL)-10, IL-6, and tumor necrosis factor (TNF)-α concentrations were measured by enzyme-linked immunosorbent assays in 191 CU patients and 89 healthy controls. The effect of LCN2 on N-formyl-methionine-leucine-phenylalanine (fMLP)-induced neutrophil chemotaxis was assessed using migration assays. CU severity was assessed based on the urticaria activity score (UAS). To explore relationships between adipokines and UAS and the chronic urticaria-specific quality of life (CU-QoL) questionnaire, a structural equation model was used. Results: Mean levels of serum LCN2, TNF-α, IL-6, and IL-10 were significantly higher in CU patients than in controls. Adiponectin levels were significantly lower in patients with CU than in controls. While serum IL-6 levels were significantly higher in refractory CU patients, compared to responsive CU individuals, LCN2 levels were significantly lower. LCN2 inhibited fMLP-induced neutrophil migration. LCN2 showed a direct relationship with UAS (β = -0.274, p < 0.001), and UAS was found to contribute to CU-QoL (β = 0.417, p < 0.001). Conclusions: Our results highlighted an imbalance in pro- and anti-inflammatory adipokines in CU patients. We suggest that LCN2 could be a differential marker for disease activity and the clinical responses to antihistamine treatment in CU patients. Modulation of systemic inflammation may be a therapeutic strategy for treating severe, refractory CU.

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Lipocalin‐2 (NGAL/LCN2), a “help‐me” signal in organ inflammation

Cited by 38 publications

References 6 publications

Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice

Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice

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

Altered Systemic Adipokines in Patients with Chronic Urticaria

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