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Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor κB signalling in rat skeletal muscle cells by AMP-activated protein kinase.
Biochem J 2011; 435(2):463-74BJ

Abstract

Sustained over-supply of saturated non-esterified 'free' fatty acids has been shown to promote skeletal muscle insulin resistance, which may be driven, in part, by an increase in inflammatory signalling within this tissue. In the present manuscript we show that exposure of L6 myotubes to palmitate, a saturated fatty acid, induces activation of the NF-κB (nuclear factor κB) pathway {based on increased IKK [IκB (inhibitory κB) kinase] phosphorylation, IκBα loss and elevated interleukin-6 mRNA expression} and that this was associated with enhanced phosphorylation/activation of p38 MAPK (mitogen-activated protein kinase), JNK (c-Jun N-terminal kinase) and ERK (extracellular-signal-regulated kinase) as well as impaired insulin-dependent activation of PKB (protein kinase B)/Akt and glucose transport. NF-κB activation by palmitate was unaffected by pharmacological inhibition of p38 MAPK or JNK, but was suppressed significantly by inhibition of MEK (MAPK/ERK kinase)/ERK signalling. The importance of ERK with respect to downstream NF-κB signalling was underscored by the finding that PMA, a potent ERK activator, enhanced IKK phosphorylation. Strikingly, both palmitate- and PMA-induced activation of IKK/NF-κB were antagonized by AMPK (AMP-activated protein kinase) activators because of reduced ERK signalling. Although palmitate-induced activation of NF-κB was repressed by AMPK activation and by cellular overexpression of a mutated IκBα (S32A/S36A) super-repressor, this did not ameliorate the loss in insulin-stimulated PKB activation or glucose transport. Our results from the present study indicate that ERK plays a pivotal role in palmitate-induced activation of the IKK/NF-κB signalling axis and that AMPK can restrain the activity of this pro-inflammatory pathway. The finding that insulin resistance persists in myotubes in which NF-κB signalling has been repressed implies that palmitate and/or its lipid derivatives retain the capacity to impair insulin-regulated events independently of the increase in inflammatory signalling.

Authors+Show Affiliations

Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21323644

Citation

Green, Charlotte J., et al. "Counter-modulation of Fatty Acid-induced Pro-inflammatory Nuclear Factor κB Signalling in Rat Skeletal Muscle Cells By AMP-activated Protein Kinase." The Biochemical Journal, vol. 435, no. 2, 2011, pp. 463-74.
Green CJ, Macrae K, Fogarty S, et al. Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor κB signalling in rat skeletal muscle cells by AMP-activated protein kinase. Biochem J. 2011;435(2):463-74.
Green, C. J., Macrae, K., Fogarty, S., Hardie, D. G., Sakamoto, K., & Hundal, H. S. (2011). Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor κB signalling in rat skeletal muscle cells by AMP-activated protein kinase. The Biochemical Journal, 435(2), pp. 463-74. doi:10.1042/BJ20101517.
Green CJ, et al. Counter-modulation of Fatty Acid-induced Pro-inflammatory Nuclear Factor κB Signalling in Rat Skeletal Muscle Cells By AMP-activated Protein Kinase. Biochem J. 2011 Apr 15;435(2):463-74. PubMed PMID: 21323644.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor κB signalling in rat skeletal muscle cells by AMP-activated protein kinase. AU - Green,Charlotte J, AU - Macrae,Katherine, AU - Fogarty,Sarah, AU - Hardie,D Grahame, AU - Sakamoto,Kei, AU - Hundal,Harinder S, PY - 2011/2/18/entrez PY - 2011/2/18/pubmed PY - 2011/9/17/medline SP - 463 EP - 74 JF - The Biochemical journal JO - Biochem. J. VL - 435 IS - 2 N2 - Sustained over-supply of saturated non-esterified 'free' fatty acids has been shown to promote skeletal muscle insulin resistance, which may be driven, in part, by an increase in inflammatory signalling within this tissue. In the present manuscript we show that exposure of L6 myotubes to palmitate, a saturated fatty acid, induces activation of the NF-κB (nuclear factor κB) pathway {based on increased IKK [IκB (inhibitory κB) kinase] phosphorylation, IκBα loss and elevated interleukin-6 mRNA expression} and that this was associated with enhanced phosphorylation/activation of p38 MAPK (mitogen-activated protein kinase), JNK (c-Jun N-terminal kinase) and ERK (extracellular-signal-regulated kinase) as well as impaired insulin-dependent activation of PKB (protein kinase B)/Akt and glucose transport. NF-κB activation by palmitate was unaffected by pharmacological inhibition of p38 MAPK or JNK, but was suppressed significantly by inhibition of MEK (MAPK/ERK kinase)/ERK signalling. The importance of ERK with respect to downstream NF-κB signalling was underscored by the finding that PMA, a potent ERK activator, enhanced IKK phosphorylation. Strikingly, both palmitate- and PMA-induced activation of IKK/NF-κB were antagonized by AMPK (AMP-activated protein kinase) activators because of reduced ERK signalling. Although palmitate-induced activation of NF-κB was repressed by AMPK activation and by cellular overexpression of a mutated IκBα (S32A/S36A) super-repressor, this did not ameliorate the loss in insulin-stimulated PKB activation or glucose transport. Our results from the present study indicate that ERK plays a pivotal role in palmitate-induced activation of the IKK/NF-κB signalling axis and that AMPK can restrain the activity of this pro-inflammatory pathway. The finding that insulin resistance persists in myotubes in which NF-κB signalling has been repressed implies that palmitate and/or its lipid derivatives retain the capacity to impair insulin-regulated events independently of the increase in inflammatory signalling. SN - 1470-8728 UR - https://www.unboundmedicine.com/medline/citation/21323644/Counter_modulation_of_fatty_acid_induced_pro_inflammatory_nuclear_factor_κB_signalling_in_rat_skeletal_muscle_cells_by_AMP_activated_protein_kinase_ L2 - https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BJ20101517 DB - PRIME DP - Unbound Medicine ER -