Abstract
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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease throughout the world
After characterization of roles in which Nod-like receptor protein 3 (NLRP3) inflammasomes play in nonalcoholic steatohepatitis (NASH), we examined whether Fufang Zhenzhu Tiaozhi (FTZ) prevents NASH development by targeting the effects of NLRP3 inflammasome activation on both inflammatory response and steatosis in the liver
Quantitation of the NLRP3 colocalization by measurement of correlation coefficient is presented in Figure 1(b), showing that NLRP3 inflammasome formation was significantly enhanced in mice on the high-fat diet (HFD) diet compared to mice on the ND and this enhanced NLRP3 inflammasome formation in the liver of mice on the HFD was significantly attenuated by FTZ
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease throughout the world. We hypothesized that hepatitis and consequent fibrosis and liver steatosis in the progression of NASH may be triggered or modulated by NLRP3 inflammasome activation In this regard, recent studies demonstrated that in addition to classical inflammatory cytokines such as IL-1β and IL-18, HMGB1 released during NLRP3 inflammasome activation is importantly implicated in both liver steatosis and subsequent hepatitis or fibrosis [8,9,10]. Recent studies demonstrated that in addition to classical inflammatory cytokines such as IL-1β and IL-18, HMGB1 released during NLRP3 inflammasome activation is importantly implicated in both liver steatosis and subsequent hepatitis or fibrosis [8,9,10] These inflammatory and uncanonical or noninflammatory effects of NLRP3 inflammasomes on the development of NASH has been the main theme in the present study
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