MLKL contributes to Western diet-induced liver injury through inhibiting autophagy.

Macroautophagy/autophagy is critical in maintaining cellular functions and homeostasis. Dynamic regulation of autophagy is associated with development of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH); however, the mechanisms involved in the regulation of autophagy in NAFLD/NASH are not well understood. Here we discuss our recent work identifying MLKL as an important nexus between autophagy and necroptosis in models of NAFLD/NASH. Mlkl, but not Ripk3, deficiency protects mice from Western diet-induced liver injury. Mlkl deficiency also prevents the accumulation of SQSTM1/p62 and LC3-II in liver in response to Western diet feeding or challenge with the protease inhibitor leupeptin. Western diet increases expression, phosphorylation and oligomerization of MLKL. In hepatocytes, palmitic acid (PA) induces the expression and translocation of MLKL to autophagosomes prior to the plasma membrane. Importantly, Mlkl, but not Ripk3, deficiency prevents the inhibition of autophagy by PA or chloroquine in hepatocytes. In contrast, overexpression of Mlkl blocks autophagic flux. Importantly, inhibition of autophagy by leupeptin or chloroquine triggers MLKL translocation to the plasma membrane, suggesting that MLKL is intimately involved in the regulation of autophagy under multiple conditions. These data indicate that MLKL contributes to Western diet-induced liver injury through inhibition of autophagy and induction of necroptosis.