The impairment of autophagic function is involved in the progression of alcoholic and non-alcoholic liver diseases.

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Yamashina S1, Ikejima K1, Inami Y1, Izumi K1, Fukuo Y1, Nakadera E1, Fukada H1, Uchiyama A1, Kon K1, Watanabe S1
1Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
Autophagy, one of protein degradation system, contributes to maintain cellular homeostasis and cell defense. Loss of autophagy in mice induces inclusion formation composed of keratins, ubiquitin, and p62 in hepatocytes. Mallory-Denk bodies represent hepatic inclusions observed in diverse chronic liver diseases such as alcoholic and non-alcoholic steatohepatitis. Recent evidences indicated that autophagic dysfunction plays a pivotal role on the progression of alcoholic and non-alcoholic liver diseases. Here, we disclose the data that hepatic steatosis impairs autophagic function in both hepatocytes and Kupffer cells. Though induction of autophagosome was suppressed in hepatocytes isolated from NAFLD model mice, accumulation of autophagosomes is observed in hepatocytes from NAFLD model. The clearance of autolysosomes was blunted in hepatocytes from NAFLD model. Both proteinase activity and expression of cathepsin B and L in autolysosomes was down-regulated by hepatic steatosis. Furthermore, rate of LysoTracker Red-stained acidic autophagosomes in hepatocytes was also suppressed by hepatic steatosis. The protein and mRNA level of the lysosomal proton-pumping vacuolar ATPase subunit ATP6v1a, ATP6v1b, ATP6v1d were suppressed in the liver from obese mice more than control. These results indicated that lipid accumulation blunts autophagic proteolysis via impairment of autophagic acidification and cathepsin expression. On the other hand, incubation with LPS increased LC3-II expression of Kupffer cells from control mice; however, an increase in LC3-II expression due to LPS was suppressed in Kupffer cells from NAFLD model mice. Both p62 expression and TNFα production in Kupffer cells from NAFLD model was higher than control mice. TNFα production by Kupffer cells from liver-specific autophagy-deficient mice due to LPS was increased to about 1.5-fold of wild type Kupffer cells. These results indicated that suppression of autophagy by hepatic steatosis sensitizes Kupffer cells to endotoxin. In conclusion, impairment of autophagic function is implicated in the pathogenesis of alcoholic and non-alcoholic steatohepatitis.