Abstract
Our previous studies have demonstrated that inhibition of glycogen synthase kinase 3β (GSK3β) activity protects mice from acute liver failure (ALF), whereas its protective and regulatory mechanism remains elusive. Autophagy is a recently recognized rudimentary cellular response to inflammation and injury. The aim of the present study was to test the hypothesis that inhibition of GSK3β mediates autophagy to inhibit liver inflammation and protect against ALF. In ALF mice model induced by d-galactosamine (d-GalN) and lipopolysaccharide (LPS), autophagy was repressed compared with normal control, and d-GalN/LPS can directly induce autophagic flux in the progression of ALF mice. Autophagy activation by rapamycin protected against liver injury and its inhibition by 3-methyladenine (3-MA) or autophagy gene 7 (Atg7) small interfering RNA (siRNA) exacerbated liver injury. The protective effect of GSK3β inhibition on ALF mice model depending on the induction of autophagy, because that inhibition of GSK3β promoted autophagy in vitro and in vivo, and inhibition of autophagy reversed liver protection and inflammation of GSK3β inhibition. Furthermore, inhibition of GSK3β increased the expression of peroxisome proliferator-activated receptor α (PPARα), and the downregulated PPARα by siRNA decreased autophagy induced by GSK3β inhibition. More importantly, the expressions of autophagy-related gene and PPARα are significantly downregulated and the activity of GSK3β is significantly upregulated in liver of ALF patients with hepatitis B virus. Thus, we have demonstrated the new pathological mechanism of ALF that the increased GSK3β activity suppresses autophagy to promote the occurrence and development of ALF by inhibiting PPARα pathway.
Highlights
Glycogen synthase kinases 3 are a group of ubiquitously expressed serine/threonine kinases that are initially found to regulate glycogen synthesis
We found that massive hepatic injury was apparent after 4–6 h as revealed by gross morphology of the liver; and the liver tissue of mice appears spotty hemorrhage at 2 h; the increased inflammation, hepatic lobules disorder, a large number of inflammatory cell infiltration and visible hepatocyte apoptosis or confluent necrosis are shown at 4 h; there are a lot of visible large necrosis areas in the liver tissue, the entire liver congestion at 6 h (Figure 1a)
We demonstrated that autophagy is suppressed in D-GalN/LPS-induced Acute liver failure (ALF) mice and ALF patients induced by hepatitis B virus (HBV) infection
Summary
Glycogen synthase kinases 3 are a group of ubiquitously expressed serine/threonine kinases that are initially found to regulate glycogen synthesis. The study has showed that inhibition of hepatocyte autophagy increases TNFα-dependent liver injury by promoting caspase-8 activation.[22] So, we hypothesized that inhibition of GSK3β may promote autophagy to protect mice from ALF. To test these hypotheses, we used the ALF model induced by the co-injection of D-galactosamine (D-GalN) and lipopolysaccharide (LPS), which has been widely used to examine the underlying mechanisms of ALF,[23,24] to explore the protective mechanisms of GSK3β inhibition and its regulatory pathway in the. Our findings demonstrate that inhibition of GSK3β increase autophagy to alleviate liver inflammation and protect mice from ALF mediated by peroxisome proliferator-activated receptor α (PPARα)
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