PMID- 20959532
OWN - NLM
STAT- MEDLINE
DCOM- 20110131
LR  - 20220317
IS  - 1522-1555 (Electronic)
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 300
IP  - 1
DP  - 2011 Jan
TI  - Free fatty acids in the presence of high glucose amplify monocyte inflammation 
      via Toll-like receptors.
PG  - E145-54
LID - 10.1152/ajpendo.00490.2010 [doi]
AB  - 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-kappaB 
      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 muM) and glucose (5-20 mM) for 
      evaluation of TLR2, TLR4, NF-kappaB, IL-1beta, 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-kappaB activity, IL-1beta, 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-kappaB activity and decreased IL-1beta and 
      MCP-1 expression. Silencing TLR2, TLR4, and p47phox with small inhibitory RNAs 
      (siRNAs) significantly reduced superoxide release, NF-kappaB activity, IL-1beta, 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-kappaB activity, and induced proinflammatory factor release.
FAU - Dasu, Mohan R
AU  - Dasu MR
AD  - Laboratory for Atherosclerosis and Metabolic Research, University of California 
      Davis Medical Center, Sacramento, CA 95817, USA. ravi.dasu@ucdmc.ucdavis.edu
FAU - Jialal, Ishwarlal
AU  - Jialal I
LA  - eng
GR  - K24-AT-00596/AT/NCCIH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20101019
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Fatty Acids, Nonesterified)
RN  - 0 (IL1B protein, human)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Lipopolysaccharide Receptors)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (TLR2 protein, human)
RN  - 0 (TLR4 protein, human)
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Toll-Like Receptors)
RN  - EC 1.6.3.- (NADPH Oxidases)
SB  - IM
MH  - Cell Line
MH  - Diabetes Mellitus, Type 2/physiopathology
MH  - Enzyme Inhibitors/pharmacology
MH  - Fatty Acids, Nonesterified/*metabolism
MH  - Gene Expression Regulation
MH  - HEK293 Cells
MH  - Humans
MH  - Hyperglycemia/metabolism/*physiopathology
MH  - Inflammation Mediators/*metabolism
MH  - Interleukin-1beta/metabolism
MH  - Lipopolysaccharide Receptors/metabolism
MH  - Monocytes/drug effects/*metabolism
MH  - NADPH Oxidases/antagonists & inhibitors
MH  - NF-kappa B/metabolism
MH  - RNA, Messenger/metabolism
MH  - RNA, Small Interfering
MH  - Reactive Oxygen Species/metabolism
MH  - Toll-Like Receptor 2/genetics/metabolism
MH  - Toll-Like Receptor 4/genetics/metabolism
MH  - Toll-Like Receptors/*metabolism
PMC - PMC3023203
EDAT- 2010/10/21 06:00
MHDA- 2011/02/01 06:00
PMCR- 2012/01/01
CRDT- 2010/10/21 06:00
PHST- 2010/10/21 06:00 [entrez]
PHST- 2010/10/21 06:00 [pubmed]
PHST- 2011/02/01 06:00 [medline]
PHST- 2012/01/01 00:00 [pmc-release]
AID - ajpendo.00490.2010 [pii]
AID - E-00490-2010 [pii]
AID - 10.1152/ajpendo.00490.2010 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2011 Jan;300(1):E145-54. doi: 
      10.1152/ajpendo.00490.2010. Epub 2010 Oct 19.