Palmitic acid elicits hepatic stellate cell activation through inflammasomes and hedgehog signaling

Na Na Duan, Xue Jing Liu, Jian Wu

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Aims Activation of hepatic stellate cells (HSCs) plays a pivotal role at the center of the fibrogenic progression in nonalcoholic steatohepatitis (NASH). However, it is poorly understood that how various molecules interact within HSCs during the progression of NASH to fibrosis. The aim of the present study is to delineate how inflammasome molecules, hedgehog signaling and autophagy provoke HSC activation using palmitic acid (PA) as a major insult. Main methods Inflammasome activation, hedgehog signaling activity and autophagy in PA-exposed HSCs were determined to investigate their role in activation of human and rodent HSC lines or primary HSCs. Key findings PA treatment elicited HSC activation reflected by increased mRNA levels of transforming growth factor-β1, connective tissue growth factor, tissue inhibitor of metalloproteinase-1 and procollagen type I (α1). In addition, expression levels of NOD-like receptor protein 3 (NLRP3) and hedgehog signaling transcription factor Gli-1 were increased in PA-exposed HSCs. It's evident that PA treatment resulted in increased production of light chain 3-II and autophagosomes, as well as enhanced autophagy flux reflected by transduction of an adeno-associated viral vector. Whereas, reduced autophagy, which is often seen in the late stage of NASH, provoked inflammasome activation. Moreover, suppressing the Hh signaling pathway by LDE225 blocked production of light chain 3-II and autophagy flux. Significance Saturated fatty acids, such as PA, stimulate HSC activation through inflammasomes and hedgehog signaling. Meanwhile, compromised autophagy may facilitate HSC activation, implicating valuable candidates for pharmacologic intervention against the progression of fibrogenesis in NASH.

Original languageEnglish (US)
Pages (from-to)42-53
Number of pages12
JournalLife Sciences
Volume176
DOIs
StatePublished - May 1 2017
Externally publishedYes

    Fingerprint

Keywords

  • Autophagy, nonalcoholic steatohepatitis
  • Hedgehog signaling
  • Hepatic stellate cells
  • NLRP3

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this