Pancreatic stellate cell activation is regulated by fatty acids and ER stress

Yael Ben-Harosh, Mariana Anosov, Hagit Salem, Yekaterina Yatchenko, R. Birk

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Introduction Pancreatic pathologies are characterized by a progressive fibrosis process. Pancreatic stellate cells (PSC) play a crucial role in pancreatic fibrogenesis. Endoplasmic reticulum (ER) stress emerges as an important determinant of fibrotic remodeling. Overload of fatty acids (FA), typical to obesity, may lead to lipotoxic state and cellular stress. Aim To study the effect of different lipolytic challenges on pancreatic ER stress and PSC activation. Methods Primary PSCs were exposed to different FAs, palmitate (pal) and oleate (ole), at pathophysiological concentrations typical to obese state, and in acute caerulein-induced stress (cer). PSC activation and differentiation were analyzed by measuring fat accumulation (oil-red staining and quantitation), proliferation (cells count) and migration (wound- healing assay). PSC differentiation markers (α-sma, fibronectin, tgf-β and collagen secretion), ER stress unfolded protein response and immune indicators (Xbp1, CHOP, TNF-α IL-6) were analyzed at the transcript and protein expression levels (quantitative RT-PCR and western blotting). Results PSC exposure to pal and ole FAs (500 µM) increased significantly fat accumulation. Proliferation and migration analysis demonstrated that ole FA retained PSC activation, while exposure to pal FA significantly halted proliferation rate and delayed migration. Cer significantly augmented PSC differentiation markers α- sma, fibronectin and collagen, and ER stress and inflammation markers including Xbp1, CHOP, TNF-α and IL-6. The ole FA treatment significantly elevated PSC differentiation markers α-sma, fibronectin and collagen secretion. PSC ER stress was demonstrated following pal treatment with significant elevation of Xbp1 splicing and CHOP levels. Conclusion Exposure to pal FA halted PSC activation and differentiation and elevated ER stress markers, while cer and ole exposure significantly induced activation, differentiation and fibrosis. Thus, dietary FA composition should be considered and optimized to regulate PSC activation and differentiation in pancreatic pathologies.

Original languageEnglish
Pages (from-to)76-85
Number of pages10
JournalExperimental Cell Research
Volume359
Issue number1
DOIs
StatePublished - 1 Oct 2017
Externally publishedYes

Keywords

  • Endoplasmic reticulum (ER) stress
  • Fatty acids
  • Fibrogenesis
  • Pancreatic stellate cells (PSC)
  • Pancreatitis

ASJC Scopus subject areas

  • Cell Biology

Fingerprint

Dive into the research topics of 'Pancreatic stellate cell activation is regulated by fatty acids and ER stress'. Together they form a unique fingerprint.

Cite this