Gα12 overexpression induced by miR16 dysregulation contributes to liver fibrosis by promoting autophagy in hepatic stellate cells.

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Gα12 overexpression induced by miR16 dysregulation contributes to liver fibrosis by promoting autophagy in hepatic stellate cells.

J Hepatol. 2017 Oct 25;:

Authors: Kim KM, Han CY, Kim JY, Cho SS, Kim YS, Koo JH, Lee JM, Lim SC, Kang KW, Kim JS, Hwang SJ, Ki SH, Kim SG

Abstract
BACKGROUND & AIMS: Hepatic stellate cells (HSCs) play a role in liver fibrosis. Guanine nucleotide-binding α-subunit12 (Gα12) converges signals from G protein-coupled receptors whose ligand levels are elevated in the environment during liver fibrosis; however, information is lacking on the effect of Gα12 on HSC trans-differentiation. This study investigated whether Gα12 is overexpressed in HSCs and, if so, its effect on liver fibrosis and the molecular basis.
METHODS: Gα12 expression was assessed by immunostaining, and immunoblot analyses of mouse fibrotic liver tissues and primary HSCs. The role of Gα12 for liver fibrosis was estimated using toxicant injury mouse model with Gα12 gene knockout and/or HSC-specific Gα12 delivery using lentiviral vectors, and primary HSCs and LX-2 cells with microRNA (miR) inhibitor, overexpression vectors, or adenoviruses. miR-16, Gα12, and LC3 were examined in fibrosis patient samples.
RESULTS: Gα12 was overexpressed in activated HSCs and fibrotic liver, and was colocalized with desmin. In a CCl4-induced fibrosis mouse model, Gα12 ablation prevented increases in fibrosis and liver injury. This effect was attenuated by HSC-specific lentiviral delivery of Gα12. Moreover, Gα12 activation promoted autophagy accompanying JNK-dependent ATG12-5 conjugation. In addition, we found that miR-16 was a direct inhibitor of de novo synthesis of Gα12. Modulations of miR-16 altered autophagy in HSCs. In a fibrosis animal model or patients with severe fibrosis, miR-16 levels were lower than their corresponding controls. Consistently, cirrhotic patient liver tissues showed Gα12 and LC3 up-regulation in desmin-positive areas.
CONCLUSIONS: MiR-16 dysregulation in HSCs causes Gα12 overexpression, which activates HSCs by facilitating autophagy through ATG12-5 formation, implying that Gα12 and the regulatory molecules may serve targets in the amelioration of liver fibrosis.
LAY SUMMARY: Gα12 is up-regulated in activated HSCs as a consequence of dysregulation of a specific microRNA abundant in HSCs, facilitating the progression of liver fibrosis. This event is mediated by JNK-dependent ATG12-5 formation and promotion of autophagy. We suggest that Gα12 and associated regulators may serve as new targets in HSCs for treatment of liver fibrosis.

PMID: 29080810 [PubMed - as supplied by publisher]

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