News Update on Lipocalin: Jan 2021

The lipocalin protein family: structural and sequence overview

Lipocalins are remarkably diverse at the sequence level yet have highly conserved structures. Most lipocalins share three characteristic conserved sequence motifs – the kernel lipocalins – while others are more divergent family members – the outlier lipocalins – typically sharing only one or two. This classification is a useful tool for analysing the family, and within these large sets are smaller groups sharing much higher levels of sequence similarity. The lipocalins are also part of a larger protein superfamily: the calycins, which includes the fatty acid binding proteins, avidins, a group of metalloproteinase inhibitors, and triabin. The superfamily is characterised by a similar structure (a repeated +1 topology β-barrel) and by the conservation of a remarkable structural signature. [1]

Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron

Although iron is required to sustain life, its free concentration and metabolism have to be tightly regulated1. This is achieved through a variety of iron-binding proteins including transferrin and ferritin2. During infection, bacteria acquire much of their iron from the host by synthesizing siderophores that scavenge iron and transport it into the pathogen3,4. We recently demonstrated that enterochelin, a bacterial catecholate siderophore, binds to the host protein lipocalin 2 (ref. 5). Here, we show that this event is pivotal in the innate immune response to bacterial infection. Upon encountering invading bacteria the Toll-like receptors on immune cells stimulate the transcription, translation and secretion of lipocalin 2; secreted lipocalin 2 then limits bacterial growth by sequestrating the iron-laden siderophore. Our finding represents a new component of the innate immune system and the acute phase response to infection. [2]

Dual Action of Neutrophil Gelatinase–Associated Lipocalin

Neutrophil gelatinase–associated lipocalin (NGAL) is expressed and secreted by immune cells, hepatocytes, and renal tubular cells in various pathologic states. NGAL exerts bacteriostatic effects, which are explained by its ability to capture and deplete siderophores, small iron-binding molecules that are synthesized by certain bacteria as a means of iron acquisition. Consistently, NGAL deficiency in genetically modified mice leads to an increased growth of bacteria. However, growing evidence suggests effects of the protein beyond fighting microorganisms. NGAL acts as a growth and differentiation factor in multiple cell types, including developing and mature renal epithelia, and some of this activity is enhanced in the presence of siderophore:iron complexes. This has led to the hypothesis that eukaryotes might synthesize siderophore-like molecules that bind NGAL. Accordingly, NGAL-mediated iron shuttling between the extracellular and intracellular spaces may explain some of the biologic activities of the protein. Interest in NGAL has been sparked by the observation that NGAL is massively upregulated after renal tubular injury and may participate in limiting kidney damage. This review summarizes the current knowledge about the dual effects of NGAL as a siderophore:iron-binding protein and as a growth factor and examines the role of these effects in renal injury. [3]

Limitations of Conventional Parameters and Role of Urinary Protein Biomarkers in the Determination of Drug Induced Acute Kidney Injury in Very Early Stage

Drug-induced Acute Kidney Injury (AKI) constitutes an important cause of acute renal failure and chronic kidney disease in present day clinical practice. Drug-induced acute renal failure (ARF) accounted for 20% of all ARF in an Indian study. The incidence and prevalence of chronic kidney disease (CKD) has dramatically increasing worldwide. Progression of AKI from mild or moderate to end stage may be prevented by selecting potentially effective therapies, if it is detected in very early stage. But early detection of AKI is often difficult due to paucity of early predictive noninvasive biomarkers. Development of omics technology has led to the identification of several urinary protein biomarkers and transcriptional biomarkers, which enable earlier detection of kidney injury. Urinary protein biomarkers have great benefit due to the easy or non-invasive availability of urine and many showing good predictive power. Several urinary protein biomarkers have been identified and have demonstrated superiority in detecting kidney injury in comparison to conventional parameters like serum creatinine (SCr), blood urea nitrogen (BUN) etc. These promising experimental biomarker of kidney damage require further confirmation of its use in routine clinical use. [4]

Influence of Obesity and Family History of Type 2 Diabetes Mellitus on Serum Ferritin and Insulin Levels in Young Adults

Aim: Obesity and family history of Type 2 Diabetes mellitus are the major risk factors for the development of type 2 Diabetes mellitus in youth. The purpose of this study is to investigate the association between serum ferritin and insulin resistance in healthy young obese with and without family history of type 2 Diabetes mellitus.

Place and Duration of Study: Department of Biochemistry, Rajarajeswari Medical College and Hospital, Kambipura, Bangalore, Karnataka, India, for eight months period in the year 2012.

Material and Methods:  A small group study was undertaken in 90 students who were in the age group of 17-22 years. The study population was divided into two groups based on body mass index, Group I /non-obese group (n=46) and Group II/ overweight & obese group (n=44). Fasting and postprandial blood glucose, Serum ferritin, serum insulin and lipid parameters were estimated and Homeostasis Model Assessment-Insulin resistance (HOMA-IR) was calculated for all the ninety students.

Results: Statistically significant differences in Total cholesterol (p=0.05), Triglycerides (p=0.05), serum insulin (p<0.01) and HOMA (p<0.01) were observed between the two groups. Mean serum ferritin values were increased in group II (overweight/obese) but not statistically significant. Serum insulin and serum ferritin showed a significant correlation with BMI for the whole study group.

Serum ferritin and insulin levels significantly correlated with waist to hip ratio in students with family history of Type 2 Diabetes mellitus as against individuals without family history. 59% of the obese students with family history of Diabetes mellitus had insulin resistance.

Conclusion: Our study has shown that a significant proportion of obese students with family history of type 2 diabetes mellitus had insulin resistance and elevated levels of ferritin, highlighting the importance of early screening for obesity associated co morbidities like metabolic syndrome, Type 2 Diabetes mellitus and cardiovascular diseases in these individuals. [5]

Reference

[1] Flower, D.R., North, A.C. and Sansom, C.E., 2000. The lipocalin protein family: structural and sequence overview. Biochimica et Biophysica Acta (BBA)-Protein Structure and Molecular Enzymology, 1482(1-2), pp.9-24.

[2] Flo, T.H., Smith, K.D., Sato, S., Rodriguez, D.J., Holmes, M.A., Strong, R.K., Akira, S. and Aderem, A., 2004. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature, 432(7019), pp.917-921.

[3] Schmidt-Ott, K.M., Mori, K., Li, J.Y., Kalandadze, A., Cohen, D.J., Devarajan, P. and Barasch, J., 2007. Dual action of neutrophil gelatinase–associated lipocalin. Journal of the American Society of Nephrology, 18(2), pp.407-413.

[4] Sundaram, R. S., Abhirama, B. R., Gowtham, L., Kalpana, G., Sudha, M., Thiyagarajan, T., Pushpa, S. and Priyadharsini, G. K. (2014) “Limitations of Conventional Parameters and Role of Urinary Protein Biomarkers in the Determination of Drug Induced Acute Kidney Injury in Very Early Stage”, Journal of Pharmaceutical Research International, 4(21), pp. 2463-2474. doi: 10.9734/BJPR/2014/13446.

[5] V. Shetty, H., M. R. Usha, S., Chandrika, N. and S. Manjula, K. (2014) “Influence of Obesity and Family History of Type 2 Diabetes Mellitus on Serum Ferritin and Insulin Levels in Young Adults”, International Blood Research & Reviews, 2(4), pp. 168-177. doi: 10.9734/IBRR/2014/8833.

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