Liver fatty metamorphosis and injury

– Central role of p62/SQSTM1 for liver protection and failure –

Fatty liver is one of pathological conditions such as diabetes and metabolic syndrome, and NASH, non-alcoholic steato-hepatitis, recently became an important issue as well. Especially in surgery, it is a pressing issue that postoperative hepatic failure must be avoided. We studied the mechanism of postoperative hepatic failure using fatty liver in db/db mice mutant lacking leptin-receptor. The hepatic regeneration was significantly inhibited after 2/3 hepatectomy, whereas proliferation was not inhibited. However, high value of serum AST/ALT was shown at the early stage, suggesting that the strong liver injury presented immediately after hepatectomy. To figure out the injury caused by hepatectomy, oxidative stress and the caspase-3 activity in the liver were monitored by the method of bioimaging, continuously and noninvasively. It revealed that both activities were increased and followed by strongly induced apoptosis.
In the tissue of fatty liver, the followings were observed: the enhancement of Fas/CD95 and Fas-ligand (FasL) expressions, the decrease of Akt phosphorylation, antioxidants, anti-apoptotic molecules and p62/SQSTM1 expression. We thus concluded that these factors causing oxidative stress followed by cellular injury in hepatectomy, played major role in impaired liver regeneration.
Intriguingly, we found that p62/SQSTM1 positively regulated the expression of FasL•Fas/CD95 as well as antioxidants (catalase, Ref-1, Mn-SOD), which are controlled via Keap-1/Nrf-2, in spite of liver fatty metamorphosis. These results suggest that p62/SQSTM1 inhibited by fatty metamorphosis induces oxidative stress and injury in the liver upon hepatectomy resulting in impaired liver regeneration, while the ability of cell proliferation is preserved.