NF-κB mediates lipid-induced fetuin-A expression in hepatocytes that impairs adipocyte function effecting insulin resistance
Abstract
Fetuin-A, a hepatic secretory protein, has recently been implicated in insulin resistance and Type 2 diabetes. It is an endogenous inhibitor of insulin receptor tyrosine kinase. However, regulation of fetuin-A synthesis in relation to insulin resistance is unclear. In the present paper, we report that both non-esterified ('free') fatty acids and fetuin-A coexist at high levels in the serum of db/db mice, indicating an association between them. For an in-depth study, we incubated palmitate with HepG2 cells and rat primary hepatocytes, and found enhanced fetuin-A secretion to more than 4-fold over the control. Interestingly, cell lysates from these incubations showed overexpression and activity of NF-kappaB (nuclear factor kappaB). In NF-kappaB-knockout HepG2 cells, palmitate failed to increase fetuin-A secretion, whereas forced expression of NF-kappaB released fetuin-A massively in the absence of palmitate. Moreover, palmitate stimulated NF-kappaB binding to the fetuin-A promoter resulting in increased reporter activity. These results suggest NF-kappaB to be the mediator of the palmitate effect. Palmitate-induced robust expression of fetuin-A indicates the occurrence of additional targets, and we found that fetuin-A severely impaired adipocyte function leading to insulin resistance. Our results reveal a new dimension of lipid-induced insulin resistance and open another contemporary target for therapeutic intervention in Type 2 diabetes.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The lack of exercise-induced decrease of fetuin A might be explained by its upregulation in the context of insulin resistance.
“The opposite may occur for fetuin A, whose lack of exercise-induced decrease might be explained by its upregulation in the context of insulin resistance [144,145].”
Cites
PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
Lowry, O. H., Rosebrough, N., Farr, A. L., & Randall, R. (1951) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)52451-6 · Cited by 315,771 · see citing works
Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor
Tontonoz, P., Hu, E., & Spiegelman, B. M. (1994) · Cell · doi:10.1016/0092-8674(94)90006-x · Cited by 3,533 · see citing works
Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB
Cai, D., Yuan, M., Frantz, D. F., Melendez, P. A., Hansen, L., Lee, J., & Shoelson, S. E. (2005) · Nature Medicine · doi:10.1038/nm1166 · Cited by 2,245 · see citing works
Yuan, M., Konstantopoulos, N., Lee, J., Hansen, L., Li, Z.-W., Karin, M., & Shoelson, S. E. (2001) · Science · doi:10.1126/science.1061620 · Cited by 1,884 · see citing works
Inhibition of NF-κB by Sodium Salicylate and Aspirin
Kopp, E. B., & Ghosh, S. (1994) · Science · doi:10.1126/science.8052854 · Cited by 1,765 · see citing works
Role of Fatty Acids in the Pathogenesis of Insulin Resistance and NIDDM
Boden, G. (1997) · Diabetes · doi:10.2337/diab.46.1.3 · Cited by 1,728 · see citing works
Vionnet, N., Hani, E. H., Dupont, S., Gallina, S., Francke, S., Dotte, S., de Matos, F., Durand, E., Leprêtre, F., Lecœur, C., et al. (2000) · The American Journal of Human Genetics · doi:10.1086/316887 · Cited by 679 · see citing works
Boden, G., Lebed, B., Schatz, M., Homko, C., & Lemieux, S. (2001) · Diabetes · doi:10.2337/diabetes.50.7.1612 · Cited by 597 · see citing works
Boden, G., She, P., Mozzoli, M., Cheung, P., Gumireddy, K., Reddy, P., Xiang, X., Luo, Z., & Ruderman, N. (2005) · Diabetes · doi:10.2337/diabetes.54.12.3458 · Cited by 528 · see citing works
Stefan, N., Hennige, A. M., Staiger, H., Machann, J., Schick, F., Kröber, S. M., Machicao, F. E., Fritsche, A., & Häring, H. (2006) · Diabetes Care · doi:10.2337/diacare.29.04.06.dc05-1938 · Cited by 475 · see citing works
Santomauro, A. T., Boden, G., Silva, M. E., Rocha, D. M., Santos, R. F., Ursich, M. J., Strassmann, P. G., & Wajchenberg, B. L. (1999) · Diabetes · doi:10.2337/diabetes.48.9.1836 · Cited by 431 · see citing works
Kelley, D. E., McKolanis, T. M., Hegazi, R. A. F., Kuller, L. H., & Kalhan, S. C. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00117.2003 · Cited by 426 · see citing works
Regulation of PPARγ activity during adipogenesis
Farmer, S. R. (2005) · International Journal of Obesity · doi:10.1038/sj.ijo.0802907 · Cited by 416 · see citing works
Plasma fetuin-A levels and the risk of type 2 diabetes
Stefan, N., Fritsche, A., Weikert, C., Boeing, H., Joost, H.-G., Häring, H.-U., & Schulze, M. B. (2008) · Diabetes · doi:10.2337/db08-0538 · Cited by 379 · see citing works
Improved Insulin Sensitivity and Resistance to Weight Gain in Mice Null for the Ahsg Gene
Mathews, S. T., Singh, G. P., Ranalletta, M., Cintrón, V. J., Qiang, X., Goustin, A. S., Jen, K. C., Charron, M. J., Jahnen‐Dechent, W., & Grunberger, G. (2002) · Diabetes · doi:10.2337/diabetes.51.8.2450 · Cited by 343 · see citing works
Auberger, P., Falquerho, L., Contreres, J. O., Pagès, G., Cam, G. L., Rossi, B., & Cam, A. L. (1989) · Cell · doi:10.1016/0092-8674(89)90098-6 · Cited by 321 · see citing works
Fetuin-A Induces Cytokine Expression and Suppresses Adiponectin Production
Hennige, A. M., Staiger, H., Wicke, C., Machicao, F., Fritsche, A., Häring, H.-U., & Stefan, N. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001765 · Cited by 282 · see citing works
Fetuin-A and Incident Diabetes Mellitus in Older Persons
Ix, J. H. (2008) · JAMA · doi:10.1001/jama.300.2.182 · Cited by 267 · see citing works
Srinivas, P. R., Wagner, A. S., Reddy, L. V. K., Deutsch, D. D., Leon, M. A., Goustin, A. S., & Grunberger, G. (1993) · Molecular Endocrinology · doi:10.1210/mend.7.11.7906861 · Cited by 243 · see citing works
Association of Serum Fetuin-A With Insulin Resistance in Type 2 Diabetic and Nondiabetic Subjects
Mori, K., Emoto, M., Yokoyama, H., Araki, T., Teramura, M., Koyama, H., Shoji, T., Inaba, M., & Nishizawà, Y. (2006) · Diabetes Care · doi:10.2337/diacare.29.02.06.dc05-1484 · Cited by 213 · see citing works
The nucleotide and partial amino acid sequences of rat fetuin
Rauth, G., Poeschke, O., Fink, E., Eulitz, M., Tippmer, S., Kellerer, M., Häring, H.-U., Nawratil, P., Haasemann, M., Jahnen‐Dechent, W., et al. (1992) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1992.tb16663.x · Cited by 134 · see citing works
Fetuin-null mice are protected against obesity and insulin resistance associated with aging
Mathews, S. T., Rakhade, S. N., Zhou, X., Parker, G. C., Coscina, D. V., & Grunberger, G. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.09.071 · Cited by 129 · see citing works
Lin, X., Braymer, H. D., Bray, G. A., & York, D. A. (1998) · Life Sciences · doi:10.1016/s0024-3205(98)00250-1 · Cited by 79 · see citing works
Effects of pioglitazone on serum fetuin-A levels in patients with type 2 diabetes mellitus
Mori, K., Emoto, M., Araki, T., Yokoyama, H., Lee, E., Teramura, M., Koyama, H., Shoji, T., Inaba, M., & Nishizawà, Y. (2008) · Metabolism · doi:10.1016/j.metabol.2008.04.019 · Cited by 77 · see citing works
Dey, D., Mukherjee, M., Basu, D., Datta, M., Roy, S. S., Bandyopadhyay, A., & Bhattacharya, S. (2005) · Cellular Physiology and Biochemistry · doi:10.1159/000089847 · Cited by 63 · see citing works
Self-citation?2-Heremans?Schmid glycoprotein gene polymorphisms are associated with adipocyte insulin action
Dahlman, I. A., Eriksson, P. O., Kaaman, M., Jiao, H., Lindgren, C. M., Kere, J., & Arner, P. (2004) · Diabetologia · doi:10.1007/s00125-004-1556-7 · Cited by 63 · see citing works
Lipid induced overexpression of NF-κB in skeletal muscle cells is linked to insulin resistance
Barma, P., Bhattacharya, S., Bhattacharya, A., Kundu, R., Dasgupta, S., Biswas, A., Bhattacharya, S., Roy, S. S., & Bhattacharya, S. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.11.014 · Cited by 59 · see citing works
Self-citationFetuin-A uptake in bovine vascular smooth muscle cells is calcium dependent and mediated by annexins
Chen, N. X., O’Neill, K. D., Chen, X., Duan, D., Wang, E., Sturek, M. S., Edwards, J. M., & Moe, S. M. (2006) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00303.2006 · Cited by 57 · see citing works
Chen, H., Chiu, Y.-L., Hsu, S., Pai, M., Lai, C., Peng, Y., Kao, T., Hung, K., Tsai, T., & Wu, K. (2009) · European Journal of Endocrinology · doi:10.1530/eje-08-0813 · Cited by 47 · see citing works
Wöltje, M., Tschöke, B., von Bülow, V., et al. (2006) · Journal of Molecular Endocrinology · doi:10.1677/jme.1.02001 · Cited by 36 · see citing works
Fetuin A Stabilizes m-Calpain and Facilitates Plasma Membrane Repair
Mellgren, R. L., & Huang, X. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706929200 · Cited by 33 · see citing works
Relationship between serum calcium and CA 19-9 levels in colorectal cancer
Fuszek, P. (2004) · World Journal of Gastroenterology · doi:10.3748/wjg.v10.i13.1890 · Cited by 27 · see citing works
Kenny, J. S., Kisaalita, W. S., Rowland, G. N., et al. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01029-6 · Cited by 9 · see citing works
Grunberger, G. (2010) · Taylor & Francis eBooks · doi:10.4324/9780203302958_chapter_15 · Cited by 5 · see citing works
Grunberger, G., Mathews, S. T., & Deutsch, D. D. (2002) · CRC Press eBooks · doi:10.1201/b12794-24 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance
Pal, D., Dasgupta, S., Kundu, R., Maitra, S., Das, G., Mukhopadhyay, S., Ray, S., Majumdar, S. S., & Bhattacharya, S. (2012) · Nature Medicine · doi:10.1038/nm.2851 · Cited by 922 · see citing works
The role of hepatokines in metabolism
Stefan, N., & Häring, H.-U. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.258 · Cited by 500 · see citing works
Gonzalez-Gil, A. M., & Elizondo-Montemayor, L. (2020) · Nutrients · doi:10.3390/nu12061899 · Cited by 278 · see citing works
Hepatokines and metabolism: Deciphering communication from the liver
Jensen-Cody, S. O., & Potthoff, M. J. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101138 · Cited by 252 · see citing works
Metabolic adaptation in obesity and type ii diabetes: myokines, adipokines and hepatokines
Oh, K.-J., Lee, D., Kim, W., Han, B., Lee, S., & Bae, K.-H. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms18010008 · Cited by 210 · see citing works
Fetuin-A: A novel link between obesity and related complications
Trepanowski, J. F., Mey, J., & Varady, K. A. (2015) · International Journal of Obesity · doi:10.1038/ijo.2014.203 · Cited by 161 · see citing works
Hepatokines and non-alcoholic fatty liver disease
Lebensztejn, D. M., Flisiak-Jackiewicz, M., Białokoz-Kalinowska, I., Bobrus-Chociej, A., & Kowalska, I. (2016) · Acta Biochimica Polonica · doi:10.18388/abp.2016_1252 · Cited by 90 · see citing works
“The high concentration of saturated fatty acids (via NF-kB activation) and increased blood glucose (via ERK 1 or 2 signaling pathways activation) induce the hepatic synthesis of this hepatokine (Takata et al., 2009; Dasgupta et al., 2010).”
BackgroundImplication of hepatokines in metabolic disorders and cardiovascular diseases
Jung, T. W., Yoo, H. J., & Choi, K. M. (2016) · BBA Clinical · doi:10.1016/j.bbacli.2016.03.002 · Cited by 71 · see citing works
Shen, X., Yang, L., Yan, S., Zheng, H., Liang, L., Cai, X., & Liao, M. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.05.014 · Cited by 63 · see citing works
Role of exercise-induced hepatokines in metabolic disorders
Ennequin, G., Sirvent, P., & Whitham, M. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00433.2018 · Cited by 54 · see citing works
Willis, S. A., Sargeant, J. A., Yates, T., Takamura, T., Takayama, H., Gupta, V., Brittain, E., Crawford, J., Parry, S. A., Thackray, A. E., et al. (2020) · The Journal of Nutrition · doi:10.1093/jn/nxz333 · Cited by 34 · see citing works
A polyphenol rescues lipid induced insulin resistance in skeletal muscle cells and adipocytes
Gogoi, B., Chatterjee, P., Mukherjee, S., Buragohain, A. K., Bhattacharya, S., & Dasgupta, S. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.08.079 · Cited by 28 · see citing works
Self-citation
- Authors
- Dasgupta, S., Bhattacharya, S., Biswas, A., Majumdar, S. S., Mukhopadhyay, S., Ray, S., & Bhattacharya, S.
- Affiliations
- Visva-Bharati University (IN)
- National Institute of Immunology (IN)
- Institute of Post Graduate Medical Education and Research (IN)
- Corresponding author
- Dasgupta, Suman
- Bhattacharya, Sushmita
- Biswas, Anindita
- Bhattacharya, Samir
- ORCID
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2010-07-14
- Volume
- 429
- Issue
- 3
- Pages
- 451-462
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W1989150212
- Cited by
- 168
- References
- 35
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 12 · 2023: 14 · 2022: 15 · 2021: 13 · 2020: 6 · 2019: 15 · 2018: 7 · 2017: 13 · 2016: 11 · 2015: 9 · 2014: 13 · 2013: 11 · 2012: 10
- FWCI
- 6.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- fetuin-A, NF-κB, insulin resistance, type 2 diabetes, palmitate, free fatty acids, hepatocytes, adipocyte function, HepG2 cells, db/db mice
- MeSH terms
- alpha-Fetoproteins, Animals, Base Sequence, Gene Expression Regulation, Humans, Insulin Resistance, Lipids, Male, NF-kappa B, Rats, Sprague-Dawley, Adipocytes, DNA Primers, Hepatocytes, Cell Line, Tumor, Chromatin Immunoprecipitation, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
