PMID- 24488024
OWN - NLM
STAT- MEDLINE
DCOM- 20141216
LR  - 20211021
IS  - 1432-0428 (Electronic)
IS  - 0012-186X (Linking)
VI  - 57
IP  - 5
DP  - 2014 May
TI  - Inhibition of macrophage fatty acid beta-oxidation exacerbates palmitate-induced 
      inflammatory and endoplasmic reticulum stress responses.
PG  - 1067-77
LID - 10.1007/s00125-014-3173-4 [doi]
AB  - AIMS/HYPOTHESIS: Saturated fatty acids (SFAs) such as palmitate activate 
      inflammatory pathways and elicit an endoplasmic reticulum (ER) stress response in 
      macrophages, thereby contributing to the development of insulin resistance linked 
      to the metabolic syndrome. This study addressed the question of whether or not 
      mitochondrial fatty acid beta-oxidation (FAO) affects macrophage responses to SFA. 
      METHODS: We modulated the activity of carnitine palmitoyl transferase 1A (CPT1A) 
      in macrophage-differentiated THP-1 monocytic cells using genetic or 
      pharmacological approaches, treated the cells with palmitate and analysed the 
      proinflammatory and ER stress signatures. RESULTS: To inhibit FAO, we created 
      THP-1 cells with a stable knockdown (KD) of CPT1A and differentiated them to 
      macrophages. Consequently, in CPT1A-silenced cells FAO was reduced. CPT1A KD in 
      THP-1 macrophages increased proinflammatory signalling, cytokine expression and 
      ER stress responses after palmitate treatment. In addition, in human primary 
      macrophages CPT1A KD elevated palmitate-induced inflammatory gene expression. 
      Pharmacological inhibition of FAO with etomoxir recapitulated the CPT1A KD 
      phenotype. Conversely, overexpression of a malonyl-CoA-insensitive CPT1A M593S 
      mutant reduced inflammatory and ER stress responses to palmitate in THP-1 
      macrophages. Macrophages with a CPT1A KD accumulated diacylglycerols and 
      triacylglycerols after palmitate treatment, while ceramide accumulation remained 
      unaltered. Moreover, lipidomic analysis of ER phospholipids revealed increased 
      palmitate incorporation into phosphatidylethanolamine and phosphatidylserine 
      classes associated with the CPT1A KD. CONCLUSIONS/INTERPRETATION: Our data 
      indicate that FAO attenuates inflammatory and ER stress responses in SFA-exposed 
      macrophages, suggesting an anti-inflammatory impact of drugs that activate FAO.
FAU - Namgaladze, Dmitry
AU  - Namgaladze D
AD  - Faculty of Medicine, Institute of Biochemistry I/ZAFES, Goethe University 
      Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
FAU - Lips, Sebastian
AU  - Lips S
FAU - Leiker, Thomas J
AU  - Leiker TJ
FAU - Murphy, Robert C
AU  - Murphy RC
FAU - Ekroos, Kim
AU  - Ekroos K
FAU - Ferreiros, Nerea
AU  - Ferreiros N
FAU - Geisslinger, Gerd
AU  - Geisslinger G
FAU - Brune, Bernhard
AU  - Brune B
LA  - eng
GR  - U54 GM069338/GM/NIGMS NIH HHS/United States
GR  - GM006938/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140201
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Diglycerides)
RN  - 0 (Fatty Acids)
RN  - 0 (Palmitates)
RN  - 0 (Triglycerides)
RN  - EC 2.3.1.21 (CPT1A protein, human)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Carnitine O-Palmitoyltransferase/metabolism
MH  - Cell Line, Tumor
MH  - Diglycerides/metabolism
MH  - Endoplasmic Reticulum/metabolism
MH  - *Endoplasmic Reticulum Stress
MH  - Fatty Acids/*metabolism
MH  - Humans
MH  - *Inflammation
MH  - Insulin Resistance
MH  - Macrophages/*metabolism
MH  - Membrane Microdomains
MH  - Metabolic Syndrome/metabolism
MH  - Mitochondria/metabolism
MH  - Oxygen/*metabolism
MH  - Palmitates/*metabolism
MH  - Triglycerides/metabolism
EDAT- 2014/02/04 06:00
MHDA- 2014/12/17 06:00
CRDT- 2014/02/04 06:00
PHST- 2013/11/25 00:00 [received]
PHST- 2014/01/02 00:00 [accepted]
PHST- 2014/02/04 06:00 [entrez]
PHST- 2014/02/04 06:00 [pubmed]
PHST- 2014/12/17 06:00 [medline]
AID - 10.1007/s00125-014-3173-4 [doi]
PST - ppublish
SO  - Diabetologia. 2014 May;57(5):1067-77. doi: 10.1007/s00125-014-3173-4. Epub 2014 
      Feb 1.