Disposal of iron by a mutant form of lipocalin 2

Barasch, Jonathan; Hollmén, Maria; Deng, Rong; Hod, Eldad A.; Rupert, Peter B.; Abergel, Rebecca J.; Allred, Benjamin E.; Xu, Katherine; Darrah, Shaun F.; Tekabe, Yared; Perlstein, Alan; Wax, Rebecca; Bruck, Efrat; Stauber, Jacob; Corbin, Kaitlyn; Buchen, Charles; Slavkovich, Vesna; Graziano, Joseph H.; Spitalnik, Steven L.; Bao, Guan‐Hu; Strong, Roland K.; Qiu, Andong

doi:10.1038/ncomms12973

Cited by 35 publications

(30 citation statements)

References 69 publications

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“…Excessive tissue accumulation of nonpolyaminated lipocalin-2 causes vascular and cardiac dysfunctions (23,44). Certain forms of lipocalin-2 are filtered by the kidney but bypass sites of megalindependent recapture (69). Other forms are less efficiently excreted in the urine under physiological conditions (23).…”

Section: Discussionmentioning

confidence: 99%

Lipocalin-2 derived from adipose tissue mediates aldosterone-induced renal injury

et al. 2018

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Lipocalin-2 is not only a sensitive biomarker, but it also contributes to the pathogenesis of renal injuries. The present study demonstrates that adipose tissue-derived lipocalin-2 plays a critical role in causing both chronic and acute renal injuries. Four-week treatment with aldosterone and high salt after uninephrectomy (ANS) significantly increased both circulating and urinary lipocalin-2, and it induced glomerular and tubular injuries in kidneys of WT mice. Despite increased renal expression of lcn2 and urinary excretion of lipocalin-2, mice with selective deletion of lcn2 alleles in adipose tissue (Adipo-LKO) are protected from ANS- or aldosterone-induced renal injuries. By contrast, selective deletion of lcn2 alleles in kidney did not prevent aldosterone- or ANS-induced renal injuries. Transplantation of fat pads from WT donors increased the sensitivity of mice with complete deletion of Lcn2 alleles (LKO) to aldosterone-induced renal injuries. Aldosterone promoted the urinary excretion of a human lipocalin-2 variant, R81E, in turn causing renal injuries in LKO mice. Chronic treatment with R81E triggered significant renal injuries in LKO, resembling those observed in WT mice following ANS challenge. Taken in conjunction, the present results demonstrate that lipocalin-2 derived from adipose tissue causes acute and chronic renal injuries, largely independent of local lcn2 expression in kidney.

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Section: Discussionmentioning

confidence: 99%

Lipocalin-2 derived from adipose tissue mediates aldosterone-induced renal injury

et al. 2018

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“…3D) suggesting similar efficiency in iron absorption by both genotypes 31 . We next investigated the levels of serum lipocalin2 as they are known to alleviate iron over-load and disposal of iron from the host 32 and found comparable levels in the circulation of both genotypes (Fig. 4c).…”

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confidence: 95%

Increased intestinal permeability exacerbates sepsis through reduced hepatic SCD-1 activity and dysregulated iron recycling

et al. 2020

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Inflammatory bowel disease is associated with changes in the mucosal barrier, increased intestinal permeability, and increased risk of infections and sepsis, but the underlying mechanisms are incompletely understood. Here, we show how continuous translocation of gut microbial components affects iron homeostasis and facilitates susceptibility to inflammation-associated sepsis. A sub-lethal dose of lipopolysaccharide results in higher mortality in Mucin 2 deficient (Muc2 −/−) mice, and is associated with elevated circulatory iron load and increased bacterial translocation. Translocation of gut microbial components attenuates hepatic stearoyl CoA desaturase-1 activity, a key enzyme in hepatic de novo lipogenesis. The resulting reduction of hepatic saturated and unsaturated fatty acid levels compromises plasma membrane fluidity of red blood cells, thereby significantly reducing their life span. Inflammation in Muc2 −/− mice alters erythrophagocytosis efficiency of splenic macrophages, resulting in an iron-rich milieu that promotes bacterial growth. Our study thus shows that increased intestinal permeability triggers a cascade of events resulting in increased bacterial growth and risk of sepsis.

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“…Lipocalins (from Greek lipos, "fat" and calyx, "cup") are a large family of small, secreted, cup-shaped proteins (Flower 1996) that are often found in luminal or aECM compartments such as mammalian plasma (Christoffersen et al 2011;Luo et al 2015;di Masi et al 2016), urine (Barasch et al 2016), or tear film (Dartt 2011), and are clinically useful biomarkers for detecting tissue damage in the renal and vascular systems (Mishra et al 2005;Cruz et al 2012;Fischer et al 2014;Haase-Fielitz et al 2014). Lipocalins bind lipophilic cargoes including sterols, phospholipids, and sphingolipids (Watanabe et al 2014;di Masi et al 2016), and while their proposed functions are quite diverse, they include transport or sequestration of aECM lipids (Gouveia and Tiffany 2005;Christoffersen et al 2011;Dartt 2011;Yeh et al 2013) and regulation of matrix metalloproteinase activity (Yan et al 2001;Leng et al 2009).…”

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confidence: 99%

Lipocalins Are Required for Apical Extracellular Matrix Organization and Remodeling in Caenorhabditis elegans

Forman-Rubinsky¹,

Cohen²,

Sundaram

2017

Genetics

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A lipid and glycoprotein-rich apical extracellular matrix (aECM) or glycocalyx lines exposed membranes in the body, and is particularly important to protect narrow tube integrity. Lipocalins ("fat cups") are small, secreted, cup-shaped proteins that bind and transport lipophilic cargo and are often found in luminal or aECM compartments such as mammalian plasma, urine, or tear film. Although some lipocalins can bind known aECM lipids and/or matrix metalloproteinases, it is not known if and how lipocalins affect aECM structure due to challenges in visualizing the aECM in most systems. Here we show that two lipocalins, LPR-1 and LPR-3, have distinct functions in the precuticular glycocalyx of developing external epithelia. LPR-1 moves freely through luminal compartments, while LPR-3 stably localizes to a central layer of the membrane-anchored glycocalyx, adjacent to the transient zona pellucida domain protein LET-653 Like LET-653 and other glycocalyx components, these lipocalins are required to maintain the patency of the narrow excretory duct tube, and also affect multiple aspects of later cuticle organization. mutants cannot maintain a continuous excretory duct apical domain and have misshapen cuticle ridges (alae) and abnormal patterns of cuticular surface lipid staining. mutants cannot maintain a passable excretory duct lumen, properly degrade the eggshell, or shed old cuticle during molting, and they lack cuticle barrier function. Based on these phenotypes, we infer that both LPR-1 and LPR-3 are required to build a properly organized aECM, while LPR-3 additionally is needed for aECM clearance and remodeling. The glycocalyx provides a powerful system, amenable to both genetic analysis and live imaging, for investigating how lipocalins and lipids affect aECM structure.

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Disposal of iron by a mutant form of lipocalin 2

Cited by 35 publications

References 69 publications

Lipocalin-2 derived from adipose tissue mediates aldosterone-induced renal injury

Lipocalin-2 derived from adipose tissue mediates aldosterone-induced renal injury

Increased intestinal permeability exacerbates sepsis through reduced hepatic SCD-1 activity and dysregulated iron recycling

Lipocalins Are Required for Apical Extracellular Matrix Organization and Remodeling in Caenorhabditis elegans

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