p62/SQSTM1 in hepatocytes plays a protective role against the development of steatohepatitis in mice

Background: Non-alcoholic steatohepatitis (NASH) is a hepatic phenotype of metabolic syndrome and an increasingly common health problem worldwide. p62/SQSTM1 (p62) is a regulatory factor for selective autophagy, and p62-deficient mice (p62-KO) develop mature-onset obesity that causes hyperphagia (J. Neurosci, 2013). In this study, we investigated the role of p62 in the pathogenesis of NASH using the hepatocytes and adipocytes specific p62 knock-in mice (hepatocyte or adipocyte rescue).
Methods: Wild-type (WT), p62-KO, p62-hepatocyte rescue (p62-HR), and p62-adipocyte rescue mice (p62-AR) were fed the 60% HF diet for 16 weeks. 
Results: p62-KO mice showed severe obesity having been fed the HF diet, and their livers represented severe steatohepatitis in terms of inflammation and fibrosis which was rapidly developed compared with WT mice. In contrast, p62-HR mice developed severe obesity as well as p62-KO and p62-AR mice, however, the pathological state of the steatohepatitis was significantly inhibited compared with p62-KO and p62-AR mice.
Correlating well with the liver pathology, the mRNA levels of the inflammatory cytokines and the fibrogenetic genes were significantly suppressed in the livers of p62-HR mice, compared to those of p62-KO and p62-AR mice.
Conclusions: p62 deletion leads to severe steatohepatitis by the HF diet, and p62 rescue in hepatocytes inhibits the progression of steatohepatitis. Activation of p62 could be a promising target for prevention and treatment of steatohepatitis.