p63 Controls Metabolic Activation of Hepatic Stellate Cells and Fibrosis via ACC1

Inhibition of hepatic p63 ameliorates steatohepatitis with fibrosis in mice

“…Of note, the involvement of p63 in the progression of steatohepatitis with fibrosis seems to be specific to the TA isoform, as ΔNp63 lacks the TA domain and has opposite effects as TAp63 [ [39] , [40] , [41] ]. Consistent with previous studies showing that TAp63 but not ΔNp63 modulates lipid accumulation in hepatocytes [ 14 ] and fibrogenesis in stellate cells [ 24 ], now we found that the inhibition of TAp63 in the liver of mice exhibiting steatohepatitis with fibrosis exert beneficial effects in the disease progression. This is in line with the fact that the expression of TAp63 and ΔNp63 are controlled by distinct mechanisms in liver cells playing different biological roles since the former exhibit a truncated TA domain even behaving in some instances as a dominant negative [ 42 ].…”

“…The knockdown of p63 in all cell types, and in particular de TA isoform in advanced stages of this chronic liver disease has a protective role. The importance of TAp63 in the development of steatohepatitis with fibrosis is in agreement with previous studies describing that i) hepatic TAp63 is already upregulated in mice with mild liver steatosis [ 14 ], ii) liver p63 in the liver and TAp63 in HSCs displays positive correlation with the NAS and other severity parameters in humans with MASLD [ 14 , 24 ], and iii) p63 expression remains high in hepatocellular carcinoma [ 37 ]. Together, this indicates that TAp63 could be involved in the progression of steatohepatitis with fibrosis throughout the whole spectrum of disease, a process governed by a complex network of mechanisms that remains to be completely understood [ 38 ].…”

“…Indeed, by using AAV8 and lentivirus, we are likely targeting various cell populations within the liver, so the observed phenotypes in mice with overexpression and knockdown of TAp63 indicate a combined result of altering this transcription factor in multiple hepatic cells. It is described that TAp63 in hepatocytes promotes triglycerides storage and inflammation [ 14 ], while TAp63 in HSCs stimulates the metabolic rewiring required for ATP production and fibrogenesis [ 24 ]. However, the potential role of TAp63 in other hepatic cell populations during the progression of steatohepatitis with fibrosis cannot be ruled out.…”

“…Regarding advanced MASH, which may be driven by very different mechanisms, the role of TAp63 remains less studied. A recent study in hepatic stellate cells (HSCs), which are the primary source of myofibroblasts that drive the fibrogenic process [ 23 ], showed that TAp63 increases in fibrogenic HSCs [ 24 ]. In addition, TAp63 protein levels in HSCs exhibit a positive correlation with both fibrosis stage and NAFLD Activity Score (NAS) in the liver of patients with MASH with fibrosis.…”

“…In addition, TAp63 protein levels in HSCs exhibit a positive correlation with both fibrosis stage and NAFLD Activity Score (NAS) in the liver of patients with MASH with fibrosis. Of note, mice lacking TAp63 in HSCs are protected against steatohepatitis with fibrosis in mice [ 24 ]. Other study showed that human liver TAp63 levels are progressively increased in MASLD, displaying positive correlation with the NAS [ 14 ].…”