Fetuin A promotes lipotoxicity in β cells through the TLR4 signaling pathway and the role of pioglitazone in anti-lipotoxicity
Abstract
Objective Fetuin A (FetA), a secreted glycoprotein, is known to affect inflammation and insulin resistance (IR) in obese humans and animals. Lipotoxicity from chronic hyperlipidemia damages pancreatic β cells, hastening the onset of diabetes. We sought to determine whether FetA promotes lipotoxicity through modulation of the toll-like receptor 4 (TLR4) inflammatory signaling pathway as well as the protective effect of pioglitazone(PIO) on lipotoxicity.Methods βTC6, a glucose-sensitive mouse pancreatic β cell line, and Sprague-Dawley rats with diet-induced obesity, were used to investigate FetA-mediated lipotoxicity. Protein expression/activation were measured by Western blotting. Small interfering (si)RNAs for TLR4 were used. Cell apoptosis was quantified by TUNEL analysis or flow cytometry, respectively. Insulin release was assessed with an insulin ELISA.Results FetA dose-dependently aggravated palmitic acid (PA)-induced βTC6 cell apoptosis, insulin secretion impairment, and inhibition of the expression of G-protein-coupled receptor 40 (GPR40) and pancreatic duodenal homeobox-1(PDX-1). Combined FetA + PA induced TLR4 expression, and subsequent inhibition of TLR4 signaling or expression was shown to prevent the strengthening effect of FetA on PA-induced lipotoxicity in βTC6 cells. FetA + PA induced p-JNK and nuclear factor-κB (NF-κB) subunit P65 expression, and inhibition of this activity reduced PA+ FetA lipotoxicity in βTC6 cells. PIO could ameliorate PA+ FetA-induced damage to βTC6 cells. Similarly, PIO improved insulin secretion disorder, reduced apoptosis, decreased FetA, TLR4, p-JNK, NF-κB subunit P65 and cleaved caspase 3 expression, and increased GPR40 and PDX-1 expression in islet β cells of diet-induced obese rats. The correlative bivariate analysis showed that increases in Fetuin A were directly proportional to the development of β cell injury.Conclusions FetA can promote lipotoxicity in β cells through the TLR4-JNK-NF-κB signaling pathway. The protective effects of PIO on lipotoxicity in β cells may involve the inhibition of the activation of the FetA and TLR4 signaling pathway.
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Fetuin A induces pancreatic β-cell toxicity.
“Fetuin A has been shown to directly induce insulin resistance [189], suppress production of adiponectin by adipocytes [148], and induce pancreatic β-cell toxicity [152].”
Fetuin-A can develop injury to pancreatic β cells, which are responsible for insulin production.
“Fetuin-A performs deleterious functions in these metabolic diseases precisely because it can develop injury to pancreatic β cells, which are responsible for insulin production [65].”
From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [65]
Fetuin-A can promote lipotoxicity in β cells through the TLR4-JNK-NF-kB signaling pathway.
“In addition to insulin resistance, fetuin-A can also promote lipotoxicity in β cells through the TLR4-JNK-NF-kB signaling pathway [65].”
From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [65]
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Mechanisms of Hepatic Insulin Resistance and Its Contribution to the Pathogenesis of Type 2 Diabetes
Onyango, A. N. (2026) · Comprehensive physiology · doi:10.1002/cph4.70285
- Authors
- Shen, X., Yang, L., Yan, S., Zheng, H., Liang, L., Cai, X., & Liao, M.
- Affiliations
- First Affiliated Hospital of Fujian Medical University (CN)
- Corresponding author
- Yang, Liyong
- Venue
- Molecular and Cellular Endocrinology
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 412
- Pages
- 1-11
- ISSN
- 0303-7207 (ISSN-L)
- OpenAlex
- W304386099
- Cited by
- 63
- References
- 30
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 9 · 2022: 9 · 2021: 5 · 2020: 5 · 2019: 7 · 2018: 2 · 2017: 5 · 2016: 1
- FWCI
- 2.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular and Cellular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81270940, 81370912)
- Natural Science Foundation of Fujian Province (2015J01453)
- Chinese Medical Association (12030460346)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- lipotoxicity, pancreatic beta cells, TLR4, pioglitazone, palmitic acid, JNK signaling, NF-κB, GPR40, PDX1, beta-cell apoptosis, insulin secretion, diet-induced obesity, type 2 diabetes, inflammation
- MeSH terms
- Pioglitazone, Insulin Secretion, Animals, Cell Line, Drug Evaluation, Preclinical, Insulin, Lipopolysaccharides, Male, Neoplasm Proteins, Obesity, Signal Transduction, Trans-Activators, Rats, Sprague-Dawley, Apoptosis, Homeodomain Proteins, Palmitic Acid, Nucleocytoplasmic Transport Proteins, Receptors, G-Protein-Coupled, Thiazolidinediones, PPAR gamma, Lipid Metabolism, Insulin-Secreting Cells, Toll-Like Receptor 4, Diet, High-Fat, alpha-2-HS-Glycoprotein
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