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

Kyu Min Kim, Chang Yeob Han, Ji Young Kim, Sam Seok Cho, Yun Seok Kim, Ja Hyun Koo, Jung Min Lee, Sung Chul Lim, Keon Wook Kang, Jae Sung Kim, Se Jin Hwang, Sung Hwan Ki, Sang Geon Kim

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59 Scopus citations


Background & aims: Hepatic stellate cells (HSCs) play a role in liver fibrosis. Guanine nucleotide-binding α-subunit12 (Gα 12 ) 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 Gα 12 on HSC trans-differentiation. This study investigated whether Gα 12 is overexpressed in HSCs and, if so, its effect on liver fibrosis and the molecular basis. Methods: Gα 12 expression was assessed by immunostaining, and immunoblot analyses of mouse fibrotic liver tissues and primary HSCs. The role of Gα 12 for liver fibrosis was estimated using toxicant injury mouse model with Gα 12 gene knockout and/or HSC-specific Gα 12 delivery using lentiviral vectors, and primary HSCs and LX-2 cells with microRNA (miR) inhibitor, overexpression vectors, or adenoviruses. miR-16, Gα 12 , and LC3 were examined in fibrosis patient samples. Results: Gα 12 was overexpressed in activated HSCs and fibrotic liver, and was colocalized with desmin. In a CCl 4 -induced fibrosis mouse model, Gα 12 ablation prevented increases in fibrosis and liver injury. This effect was attenuated by HSC-specific lentiviral delivery of Gα 12 . Moreover, Gα 12 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 Gα 12 . 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 Gα 12 and LC3 up-regulation in desmin-positive areas. Conclusions: MiR-16 dysregulation in HSCs causes Gα 12 overexpression, which activates HSCs by facilitating autophagy through ATG12-5 formation, implying that Gα 12 and the regulatory molecules may serve targets in the amelioration of liver fibrosis. Lay Summary: Gα 12 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 Gα 12 and associated regulators may serve as new targets in HSCs for treatment of liver fibrosis.

Original languageEnglish
Pages (from-to)493-504
Number of pages12
JournalJournal of Hepatology
Issue number3
StatePublished - Mar 2018


  • G protein
  • Liver fibrosis
  • activated stellate cell
  • lysosomal degradation
  • non-coding RNA


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