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Int. J. Mol. Sci. 2016, 17(11), 1878; doi:10.3390/ijms17111878

Increased Expression Profile and Functionality of TLR6 in Peripheral Blood Mononuclear Cells and Hepatocytes of Morbidly Obese Patients with Non-Alcoholic Fatty Liver Disease

1
Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
2
Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), 390008 Santander, Spain
3
Transplant and Autoimmunity Group, Research Institute Marqués de Valdecilla (IDIVAL), 39008 Santander, Spain
4
Immunology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
5
General Surgery Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Johannes Haybaeck
Received: 14 September 2016 / Revised: 31 October 2016 / Accepted: 2 November 2016 / Published: 10 November 2016
(This article belongs to the Collection Molecular Mechanisms of Human Liver Diseases)
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Abstract

Current evidence suggests that gut dysbiosis drives obesity and non-alcoholic fatty liver disease (NAFLD) pathogenesis. Toll-like receptor 2 (TLR2) and TLR6 specifically recognize components of Gram-positive bacteria. Despite the potential implications of TLR2 in NAFLD pathogenesis, the role of TLR6 has not been addressed. Our aim is to study a potential role of TLR6 in obesity-related NAFLD. Forty morbidly obese patients undergoing bariatric surgery were prospectively studied. Cell surface expression of TLR2 and TLR6 was assessed on peripheral blood mononuclear cells (PBMCs) by flow cytometry. Freshly isolated monocytes were cultured with specific TLR2/TLR6 agonists and intracellular production of cytokines was determined by flow-cytometry. In liver biopsies, the expression of TLR2 and TLR6 was analyzed by immunohistochemistry and cytokine gene expression using RT-qPCR. TLR6 expression in PBMCs from non-alcoholic steatohepatitis (NASH) patients was significantly higher when compared to those from simple steatosis. The production of pro-inflammatory cytokines in response to TLR2/TLR6 stimulation was also significantly higher in patients with lobular inflammation. Hepatocyte expression of TLR6 but not that of TLR2 was increased in NAFLD patients compared to normal liver histology. Deregulated expression and activity of peripheral TLR6 in morbidly obese patients can mirror the liver inflammatory events that are well known drivers of obesity-related NASH pathogenesis. Moreover, TLR6 is also significantly overexpressed in the hepatocytes of NAFLD patients compared to their normal counterparts. Thus, deregulated TLR6 expression may potentiate TLR2-mediated liver inflammation in NAFLD pathogenesis, and also serve as a potential peripheral biomarker of obesity-related NASH. View Full-Text
Keywords: TLR6; TLR2; non-alcoholic fatty liver disease; lobular inflammation; morbid obesity; pro-inflammatory cytokines TLR6; TLR2; non-alcoholic fatty liver disease; lobular inflammation; morbid obesity; pro-inflammatory cytokines
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Arias-Loste, M.T.; Iruzubieta, P.; Puente, Á.; Ramos, D.; Santa Cruz, C.; Estébanez, Á.; Llerena, S.; Alonso-Martín, C.; San Segundo, D.; Álvarez, L.; López Useros, A.; Fábrega, E.; López-Hoyos, M.; Crespo, J. Increased Expression Profile and Functionality of TLR6 in Peripheral Blood Mononuclear Cells and Hepatocytes of Morbidly Obese Patients with Non-Alcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2016, 17, 1878.

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