Tectorigenin alleviates intrahepatic cholestasis by inhibiting hepatic inflammation and bile accumulation via activation of PPARγ

Abstract

Background and Purpose: Increasing evidence suggests that human cholestasis is closely associated with the accumulation and activation of hepatic macrophages.Research indicates that activation of PPARγ exerts liver protective effects in cholestatic liver disease (CLD), particularly by ameliorating inflammation and fibrosis, thus limiting disease progression. However, existing PPARγ agonists, such as troglitazone and rosiglitazone, have significant side effects that prevent their clinical application in the treatment of CLD. In this study, we found that tectorigenin alleviates intrahepatic cholestasis in mice by activating PPARγ.Experimental Approach: Wild-type mice were intragastrically administered α-naphthylisothiocyanate (ANIT) or fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to simultaneously establish an experimental model of intrahepatic cholestasis and tectorigenin intervention, followed by determination of intrahepatic cholestasis and the mechanisms involved. In addition, PPARγ-deficient mice were administered ANIT and/or tectorigenin to determine whether tectorigenin exerts its liver protective effect by activating PPARγ.

Pterostilbene Alleviates Cholestasis by Promoting SIRT1 Activity in Hepatocytes and Macrophages

“…However, in the liver of ANIT-induced CLD mouse models, FXR was increased by approximately 2-, 3.82-, and 2.41-fold after treatment with 25, 50, and 100 mpk PTE, respectively ( Figure 4B ). Previous studies found that macrophage-derived inflammatory factors (IL-1β, among others) activated NF-kB-p65 in hepatocytes, resulting in binding of NF-kB-p65 to the FXR promoter region, which precluded expression of FXR ( El Kasmi et al, 2018 ; Xiang et al, 2021 ). Consistent with this, when SIRT1 was absent from BMDMs, no significant change in expression of inflammatory factors ( Ccl2 , TNF-α , Ccr2 , and IL-1β ) was observed after PTE treatment of DDC-induced CLD model mice ( Figure 7G ); however, FXR protein levels in the liver were decreased ( Figure 7I ).…”

“…Primary hepatocyte isolation was performed using a modified 2-step collagenase perfusion technique as previously reported ( Xiang et al, 2021 ). Briefly, the liver specimen was cannulated under sterile conditions and flushed once with 50 ml washing buffer containing 2.5 mM EGTA (SIGMA-Aldrich).…”

Human menstrual blood-derived stem cell transplantation suppresses liver injury in DDC-induced chronic cholestasis

“…Xiang et al suggested that tectorigenin could treat DDC-induced cholestasis by increasing BSEP expression through PPARγ. Blocking upregulation of BSEP expression prevented the therapeutic effect of PPAR on cholestasis [ 48 ]. According to Zhang et al, Yin-Zhi-Huang could significantly decrease the serum total bile acids and DBLT levels, and improve histological disorganization by regulating Oatp2, Ntcp, and Mrp2 expression in cholestatic rats [ 49 ].…”

Metabolomic Analysis Reveals the Therapeutic Effects of MBT1805, a Novel Pan-Peroxisome Proliferator-Activated Receptor Agonist, on α-Naphthylisothiocyanate-Induced Cholestasis in Mice

“…We speculated that the difference of PPARs distribution and affinity to agonist between hepatocytes and bile duct cells might provide an explanation. PPARα (Yang et al, 2019) and PPARγ (Xiang et al, 2021) have been reported to have protective effects in cholestasis by regulating bile acid metabolism in hepatocytes. In cholangiocytes, studies mainly focused on PPARγ, which played an important role in maintaining immune tolerance (Marra et al, 2005;Zhang et al, 2018).…”