Palmitate-induced Slc2a4/GLUT4 downregulation in L6 muscle cells: evidence of inflammatory and endoplasmic reticulum stress involvement

Autor(es)

Ebersbach-Silva, Patricia ^[1] ; Poletto, Ana Claudia ^[1] ; David-Silva, Aline ^[1] ; Seraphim, Patricia Monteiro ^[2] ; Anhe, Gabriel Forato ^[3] ; Passarelli, Marisa ^[4] ; Furuya, Daniela Tomie ^[1] ; Machado, Ubiratan Fabres ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Av Prof Lineu Prestes 1524, BR-05508900 Sao Paulo - Brazil

^[2] Univ Estadual Paulista, Sch Sci & Technol, Dept Phys Therapy, Sao Paulo - Brazil

^[3] Univ Estadual Campinas, Dept Pharmacol, Fac Med Sci, Campinas, SP - Brazil

^[4] Univ Sao Paulo, Hosp Clin HCFMUSP, Lab Lipides LIM 10, Fac Med, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: LIPIDS IN HEALTH AND DISEASE; v. 17, APR 2 2018.
• Citações Web of Science: 0

Resumo

Background: Obesity is strongly associated to insulin resistance, inflammation, and elevated plasma free fatty acids, but the mechanisms behind this association are not fully comprehended. Evidences suggest that endoplasmic reticulum (ER) stress may play a role in this complex pathophysiology. The aim of the present study was to investigate the involvement of inflammation and ER stress in the modulation of glucose transporter GLUT4, encoded by Slc2a4 gene, in L6 skeletal muscle cells. Methods: L6 cells were acutely (2 h) and chronically (6 and 12 h) exposed to palmitate, and the expression of several proteins involved in insulin resistance, ER stress and inflammation were analyzed. Results: Chronic and acute palmitate exposure significantly reduced GLUT4 protein (similar to 39%, P < 0.01) and its mRNA (18%, P < 0.01) expression. Only acute palmitate treatment increased GRP78 (28%, P < 0.05), PERK (98%, P < 0.01), eIF-2A (35%, P < 0.01), IRE1a (60%, P < 0.05) and TRAF2 (23%, P < 0.05) protein content, and PERK phosphorylation (106%, P < 0.001), but did not elicit eIF-2A, IKK phosphorylation or increased XBP1 nuclear content. Additionally, acute and chronic palmitate increased NFKB p65 nuclear content (similar to 30%, P < 0.05) and NFKB binding activity to Slc2a4 gene promoter (similar to 45%, P < 0.05). Conclusion: Different pathways are activated in acute and chronic palmitate induced-repression of Slc2a4/GLUT4 expression. This regulation involves activation of initial component of ER stress, such as the formation of a IRE1a-TRAF2-IKK complex, and converges to NFKB-induced repression of Slc2a4/GLUT4. These results link ER stress, inflammation and insulin resistance in L6 cells. (AU)

• Processo FAPESP: 10/09984-5 - Análise das vias da "unfolded protein response" (upr) na regulação da expressão do glut4 em células musculares tratadas com palmitato.
• Beneficiário: Patrícia Ebersbach Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/18841-1 - Regulação do metabolismo da glicose pelo osso: ações da osteocalcina na resistência à insulina e inflamação em tecidos adiposo e hepático
• Beneficiário: Daniela Tomie Furuya
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores