Mouse Hepatic Stellate Cells

The Expression of Adiponectin and Fibrotic Genes is Inversely Correlated in HSCs

Hepatic stellate cells (HSCs) drive liver fibrosis. Although adiponectin is expressed in quiescent HSCs, its local role in fibrosis progression remains unclear. Zhao's team investigated whether HSC-specific adiponectin regulates fibrosis development using an inducible transgenic mouse model.

Activated hepatic stellate cells (HSCs) are the primary source of collagen and responsible for liver fibrosis. To determine if adiponectin produced locally by HSCs regulated HSC activation, wild-type mouse HSCs were isolated and gene expression was analyzed over time. Adiponectin expression decreased rapidly within 2 hours of culture, prior to induction of fibrotic marker SMA (Fig. 1A, 1B), indicating adiponectin may inhibit expression of fibrotic genes. Leptin expression also decreased, but at a slower rate (Fig. 1C). TGF-β expression peaked initially at 2 hours then returned to baseline levels (Fig. 1D), which may be a result of activation from cell isolation. Next, they treated human LX2 HSCs with TGF-β and found increased expression of fibrotic markers SMA and COL1A1 that were reversed by treatment with adiponectin receptor agonist AdipoRon (Fig. 1E, 1F). Adiponectin knockdown in LX2 cells using CRISPR-Cas9 (>90% reduction; Fig. 1G) significantly increased baseline and TGF-β-induced expression of Tgfβ, Acta2, Col1a1, and Serpine1 (Fig. 1H-1K). Adiponectin deletion alone was sufficient to induce increases in Tgfβ and Acta2 expression. Knockdown of adiponectin also significantly induced expression of inflammatory genes TNFα, IL-1β, Ccl2, Ifnγ, and Adgre1 even in the absence of TGF-β (Fig. 1L-1P).