Diosmetin modulates lipogenesis and alleviates inflammatory response in
nonalcoholic steatohepatitis through STAT1/CXCL10-dependent pathway
Abstract
Background and Purpose: Diosmetin (Dios) exerted a hepatoprotective
effect against nonalcoholic steatohepatitis (NASH), but few reports
interpreted clearly that the alleviation of Dios against NASH were
associated with the inhibition of signal transducers and activators of
transcription 1 (STAT1) and macrophage chemotactic ligand 10 (CXCL10).
Meanwhile, the mechanism of Dios involved with STAT1/CXCL10 mediated
pathway was unknown yet. Experimental Approach: Here, high-fat diet
(HFD) and palmitic acid (PA) were used to induced NASH model in mice and
HepG2 cells, respectively. The liver RNA-Seq was used to reveal the key
targets interfered by Dios. The impacts of Dios on the expressions of
STAT1, CXCL10 and the levels of genes and proteins associated with
lipogenesis and inflammation were measured by qRT-PCR and western blot
assays. The STAT1 inhibitor, STAT1 overexpression plasmid, and CXCL10
siRNA were utilized to clarify the mechanism of Dios against NASH
through STAT1 / CXCL10. Key Results: Dios could reduce functional
parameters and morphological changes in HepG2 cells and NASH mice.
Additionally, Dios alleviated the expressions of key targets STAT1 and
CXCL10, and their downstream proteins involved with lipogenesis and
inflammation. Interestingly, NASH was ameliorated in STAT1-inhibited
mice and HepG2 cells. Unfortunately, transfecting HepG2 cells with STAT1
over-expression plasmid aggravated the development of NASH and reduced
Dios-conferred hepatoprotective effect. Conclusions and Implications:
The alleviation of Dios against NASH was through mediation of
lipogenesis and inflammatory response via STAT1/CXCL10-dependent
pathway. Therefore, Dios has good hepatoprotective effects and
potentiality as a promising therapeutic agent for NASH in clinical
application.