Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury

Abstract

Background and aims Autophagy is a critical process in cell survival and the maintenance of homeostasis. However, the implementation of therapeutic approaches based on autophagy mechanisms after liver damage is still challenging. Methods We used a hepatospecific Atg7‐deficient murine model to address this question. Results We showed that the proliferation and regeneration capacity of Atg7‐deficient hepatocytes was impaired. On the one hand, Atg7‐deficient hepatocytes showed steady‐state hyperproliferation. On the other hand, external triggers such as partial hepatectomy (PHx) or cell transplantation did not induce hepatocellular proliferation or liver repopulation. After PHx, hepatocyte proliferation was strongly decreased, accompanied by high mortality. This increase in mortality could be overcome by pharmacological mTOR inhibition. In accordance with hepatocyte hypoproliferation after damage, Atg7‐deficient hepatocytes failed to repopulate the liver in a hepatic injury model. Atg7‐deficient mice showed hepatic hypertrophy, transient cellular hypertrophy, and high transaminase levels followed by strong perisinusoidal/pericellular fibrosis with age. Their elevated modified hepatic activity index (mHAI) was almost exclusively due to apoptosis without any inflammation. These parameters were associated with variations in the triglyceride content and compromised lipid droplet formation after PHx. Mechanistically, we also observed a modulation of HGF, PAK4, NOTCH3 and YES1, which are proteins involved in cell cycle regulation. Conclusion We demonstrated the important role of autophagy in the regeneration capacity of hepatocytes. We showed the causative relationship between autophagy and triglycerides that is essential for promoting liver recovery. Finally, pharmacological mTOR inhibition overcame the impact of autophagy deficiency after liver damage and prevented mortality.

ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program

“…Recent studies have shown the importance of degradation and autophagy in regulating cell plasticity in several organs (Saera‐Vila et al , 2016; Call & Nichenko, 2020; Li et al , 2020; Romermann et al , 2020). We speculate that Stage 1 of paligenosis is not only required to change the cell structure to one that is more physiologically progenitor‐like but also to generate enough energy for DNA replication and cell division.…”

Anti-CD20 Therapy Alters the Protein Signature in Experimental Murine AIH, but Not Exclusively towards Regeneration

“…Therefore, upregulation of this factor might be one mechanism of the positive effects observed in other models [21] and diseases [5][6][7][8][9][10][11][12][13]. The same is true for the modulation of WISP-1, which is upregulated in patients and mice with fibrosis [46,47], and overexpression of WISP-1 promotes tumor growth [48]. The elusive role of Pdgfb in fibrotic diseases and systemic sclerosis has been shown [49].…”

Autophagy alleviates amiodarone-induced hepatotoxicity

“…Recently, enhanced ER stress and liver injury have been associated with impaired autophagy in murine and human NAFLD which, conversely, could be reduced by autophagy induction (González-Rodríguez et al 2014 ; Tanaka et al 2016 ; Lin et al 2013 ). Accordingly, mice with hepatocellular autophagy ( ATG7 )-deficiency revealed increased oxidative stress-induced activation of JNK and caspases as well as enhanced hepatocyte apoptosis (Wang et al 2010 ; Amir et al 2013 ; Römermann et al 2020 ). Vice versa, treatment of patients with fibrinogen storage disease, which is characterized by the accumulation of fibrinogen aggregates and enhanced ER stress in the liver, with the autophagy inducer carbamazepine resulted in increased autophagy in the liver and decreased serum levels of caspase-cleaved K18 (Puls et al 2013 ).…”