The focal adhesion kinase (FAK) participates in tauroursodeoxycholic acid (TUDCA)'s mechanism of action against endoplasmic reticulum stress in pancreatic beta cell line INS-1E

Author(s)

Lucas Rodolfo de Oliveira Rosa

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2024-07-19

Examining board members

Helena Cristina de Lima Barbosa; Jane Cristina de Souza; Leticia Ignácio de Souza Zimmermann; Fernanda Ortis; Jean Franciesco Vettorazzi

• Advisor: Helena Cristina de Lima Barbosa

Abstract

Diabetes mellitus is one of the great modern public health challenges in the world; the search for new therapies or adjuvants that can help control it is essential. Amidst the many factors involved in the progression of the disease, endoplasmic reticulum stress is of great relevance in the progression of the disfunction of pancreatic beta cells. TUDCA is capable of minimizing that stress, but its mechanisms of action are not still fully understood. In this work, we studied the possible role of FAK, a focal adhesion protein, in this mechanism. We performed our experiments in INS-1E pancreatic beta cell line, divided in three groups: Those subjected to no treatment (Control), exposed to Palmitate (0.5mM/24h) or Palmitate + TUDCA (100µM/24h). We subjected these cells additionally to knockdown of FAK by specific siRNA or Y15 pharmacological inhibitor, as well as incubation with inhibitors for the three TUDCA receptors: ?5?1-integrin, TGR5 and S1PR2. TUDCA was capable of minimizing endoplasmic reticulum stress in these cells, reducing the protein content of a stress marker, ATF4, when compared to the groups exposed solely to Palmitate. This capacity, however, was lost when cells were subjected to knockdown of FAK, or the inhibitors of the three receptors. Besides that, Palmitate led to an increase in insulin secretion, which was normalized by TUDCA treatment; however, in the condition of FAK knockdown, this ability was abolished. Therefore, our results indicate that FAK seems to be an important element of the mechanism of action of TUDCA in mitigating endoplasmic reticulum stress and promoting the normalization of insulin secretion in pancreatic beta cells, with FAK possibly acting as a common element through which signaling of all three receptors converge. This better comprehension of TUDCA effects can help make viable new perspectives of treatment against pancreatic beta cell dysfunction (AU)

• FAPESP's process: 19/23951-7 - Focal adhesion kinase (FAK) as an element of the mechanisms of action of tauroursodeoxycholic bile acid (TUDCA)
• Grantee: Lucas Rodolfo de Oliveira Rosa
• Support Opportunities: Scholarships in Brazil - Doctorate