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


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.


RESULTS
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.


CONCLUSIONS
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.
Dept. of Medical Microbiology, Key Laboratory of Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Na-Na
NN
Duan
Dept. of Medical Microbiology, Key Laboratory of Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Xue-Jing
XJ
Liu
Dept. of Medical Microbiology, Key Laboratory of Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Shanghai Institute of Liver Diseases, Fudan University, Shanghai 200032, China. Electronic address: jian.wu@fudan.edu.cn.
Jian
J
Wu
D000818:Animals; D053823:Hedgehog Proteins / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000096:biosynthesis; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology; D019308:Palmitic Acid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D000071676:Zinc Finger Protein GLI1 / Q000096:biosynthesis
C400551:GLI1 protein, human; C498521:Gli1 protein, rat; D053823:Hedgehog Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C573346:Nlrp3 protein, rat; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D000071676:Zinc Finger Protein GLI1; D019308:Palmitic Acid
Autophagy, nonalcoholic steatohepatitis; Hedgehog signaling; Hepatic stellate cells; NLRP3