Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors

Mohan R. Dasu, Ishwarlal Jialal

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Type 2 diabetes (T2DM) is characterized by hyperglycemia, dyslipidemia, and increased inflammation. Previously, we showed that high glucose (HG) induces Toll-like receptor (TLR) expression, activity, and inflammation via NF-κB followed by cytokine release in vitro and in vivo. Here, we determined how HG-induced inflammation is affected by free fatty acids (FFA) in human monocytes. THP-1 monocytic cells, CD14+ human monocytes, and transiently transfected HEK293 cells were exposed to various FFA (0-500 μM) and glucose (5-20 mM) for evaluation of TLR2, TLR4, NF-κB, IL-1β, monocyte chemoattractant protein-1 (MCP-1), and superoxide release. In THP-1 cells, palmitate increased cellular TLR2 and TLR4 expression, generated reactive oxygen species (ROS), and increased NF-κB activity, IL-1β, and MCP-1 release in a dose- and time-dependent manner. Similar data were observed with stearate and FFA mixture but not with oleate. Conversely, NADPH oxidase inhibitor treatment repressed glucose-and palmitate-stimulated ROS generation and NF-κB activity and decreased IL-1β and MCP-1 expression. Silencing TLR2, TLR4, and p47phox with small inhibitory RNAs (siRNAs) significantly reduced superoxide release, NF-κB activity, IL-1β, and MCP-1 secretion in HG and palmitate-treated THP-1 cells. Moreover, data from transient transfection experiments suggest that TLR6 is required for TLR2 and MD2 for TLR4 to augment inflammation in FFA- and glucose-exposed cells. These findings were confirmed with human monocytes. We conclude that FFA exacerbates HG-induced TLR expression and activity in monocytic cells with excess superoxide release, enhanced NF-κB activity, and induced proinflammatory factor release.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume300
Issue number1
DOIs
StatePublished - Jan 2011

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Toll-Like Receptors
Nonesterified Fatty Acids
Monocytes
Inflammation
Chemokine CCL2
Glucose
Interleukin-1
Palmitates
Superoxides
Reactive Oxygen Species
Stearates
NADPH Oxidase
HEK293 Cells
Oleic Acid
Dyslipidemias
Hyperglycemia
Type 2 Diabetes Mellitus
Transfection
RNA
Cytokines

Keywords

  • Hyperglycemia
  • Palmitate
  • Toll-like receptor 2
  • Toll-like receptor 4

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors. / Dasu, Mohan R.; Jialal, Ishwarlal.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 300, No. 1, 01.2011.

Research output: Contribution to journalArticle

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