The
Nod-like receptor protein 3 (NLRP3)
inflammasome activation not only serves as an intracellular machinery triggering
inflammation but also produces uncanonical effects beyond
inflammation such as changing cell metabolism and increasing cell membrane permeability. The present study was designed to test whether this NLRP3
inflammasome activation contributes to the "two-hit" injury during
nonalcoholic steatohepatitis (NASH) and whether it can be a therapeutic target for the action of
Fufang Zhenzhu Tiaozhi (
FTZ), a widely used herbal remedy for
hyperlipidemia and
metabolic syndrome in China. We first demonstrated that NLRP3
inflammasome formation and activation as well as
lipid deposition occurred in the liver of mice on the high-fat diet (HFD), as shown by increased NLRP3 aggregation, enhanced production of IL-1β and high mobility group box 1 (
HMGB1), and remarkable
lipid deposition in liver cells.
FTZ extracts not only significantly reduced the NLRP3
inflammasome formation and activation but also attenuated the
liver steatosis and fibrogenic phenotype changed. In in vitro studies,
palmitic acid (PA) was found to increase colocalization of NLRP3 components and enhanced caspase-1 activity in hepatic stellate cells (HSCs), indicating enhanced formation and activation of NLRP3
inflammasomes by PA. PA also increased
lipid deposition. Nlrp3
siRNA can reverse this effect by silencing the NLRP3
inflammasome and both with
FTZ. In
FTZ-treated cells, not only
inflammasome formation and activation was substantially attenuated but also
lipid deposition in HSCs was blocked. This inhibition of
FTZ on
lipid deposition was similar to the effects of
glycyrrhizin, an
HMGB1 inhibitor. Mechanistically, stimulated membrane raft redox signaling platform formation and increased O2•- production by PA to activate NLRP3
inflammasomes in HSCs was blocked by
FTZ treatment. It is concluded that
FTZ extracts inhibit NASH by its action on both inflammatory response and liver lipid metabolism associated with NLRP3
inflammasome formation and activation.