Exogenous Therapeutics of Microrna-29a Attenuates Development of Hepatic Fibrosis in Cholestatic Animal Model through Regulation of Phosphoinositide 3-Kinase p85 Alpha

Ya-Ling Yang,Hung-Yu Lin,Feng-Sheng Wang,Ying-Hsien Huang

doi:10.3390/ijms21103636

Ya-Ling Yang, Hung-Yu Lin + Show 2 more

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https://doi.org/10.3390/ijms21103636

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Recent studies have found that microRNA-29a (miR-29a) levels are significantly lower in fibrotic livers, as shown with human liver cirrhosis. Such downregulation influences the activation of hepatic stellate cells (HSC). Phosphoinositide 3-kinase p85 alpha (PI3KP85α) is implicated in the regulation of proteostasis mitochondrial integrity and unfolded protein response (UPR) and apoptosis in hepatocytes. This study aimed to investigate the potential therapeutic role of miR-29a in a murine bile duct ligation (BDL)-cholestatic injury and liver fibrosis model. Mice were assigned to four groups: sham, BDL, BDL + scramble miRs, and BDL + miR-29a-mimic. Liver fibrosis and inflammation were assessed by histological staining and mRNA/protein expression of representative markers. Exogenous therapeutics of miR-29a in BDL-stressed mice significantly attenuated glutamic oxaloacetic transaminase (GOT)/glutamic-pyruvic transaminase (GPT) and liver fibrosis, and caused a significant downregulation in markers related to inflammation (IL-1β), fibrogenesis (TGF-β1, α-SMA, and COL1α1), autophagy (p62 and LC3B II), mitochondrial unfolded protein response (UPRmt; C/EBP homologous protein (CHOP), heat shock protein 60 (HSP60), and Lon protease-1 (LONP1, a mitochondrial protease), and PI3KP85α within the liver tissue. An in vitro luciferase reporter assay further confirmed that miR-29a mimic directly targets mRNA 3′ untranslated region (UTR) of PI3KP85α to suppress its expression in HepG2 cell line. Our data provide new insights that therapeutic miR-29a improves cholestasis-induced hepatic inflammation and fibrosis and proteotstasis via blocking PI3KP85α, highlighting the potential of miR-29a targeted therapy for liver injury.

Highlights

Mounting evidence has highlighted persistent liver injury results in liver fibrosis, which involves various cell types
Activated hepatic stellate cells (HSCs) are responsible for secretion of profibrogenic mediators, transforming growth factor-β (TGF-β), and generates extracellular matrix (ECM) proteins that can worsen the wound-healing process, including collagen types I/III, fibronectin, and laminin [2]
Both bile duct ligation (BDL) + scramble and BDL + miR-29a showed an increase in liver-to-body ratio (Table 1)

Summary

Introduction

Mounting evidence has highlighted persistent liver injury results in liver fibrosis, which involves various cell types. Following a persistent liver injury, hepatic stellate cells (HSCs) are activated and experience morphologic and functional trans-differentiation into contractile myofibroblastic cells [1]. A considerable decrease of miR-29 family (a to c) in humans with liver cirrhosis and a hepatic fibrosis animal model induced by the administration of hepatotoxin has been reported. Their role in affecting HSC activation has been demonstrated. TGF-β1 causes HSC to activate, transdifferentiate, and secrete ECM through the downregulation of microRNA-29a (miR-29a) [4,5]. Evidence of whether miR-29a level is implicated in the pathogenesis of acute cholestasis is still scarce and whether exogenous miR-29a exerts therapeutic potential is yet to be investigated

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