Chuanxiong Rhizoma extracts prevent cholestatic liver injury by targeting H3K9ac-mediated and cholangiocyte-derived secretory protein PAI-1 and FN

Chuanxiong Rhizoma(CX,the dried rhizome of Ligusticum wallichii Franch.),a well-known traditional Chinese medicine,is clinically used for treating cardiovascular,cerebrovascular and hepatobiliary diseases.Cholestatic liver damage is one of the chronic liver diseases with limited effective therapeutic strategies.Currently,little is known about the mechanism links between CX-induced anti-cholestatic action and intercellular communication between cholangiocytes and hepatic stellate cells(HSCs).The study aimed to evaluate the hepatoprotective activity of different CX extracts including the aqueous,alkaloid,phenolic acid and phthalide extracts of CX(CX_(AE),CX_(AL),CX_(PA)and CX_(PHL))and investigate the intercellular communication-related mechanisms by which the most effective extracts work on cholestatic liver injury.The active compounds of different CX extracts were identified by UPLC-MS/MS.A cholestatic liver injury mouse model induced by bile duct ligation(BDL),and transforming growth factor-β(TGF-β)-treated human intrahepatic biliary epithelial cholangiocytes(HIBECs)and HSC cell line(LX-2 cells)were used for in vivo and in vitro studies.Histological and other biological techniques were also applied.The results indicated that CX_(AE),CX_(AL)and CX_(PHL)significantly reduced ductular reaction(DR)and improved liver fibrosis in the BDL mice.Meanwhile,both CX_(AE)and CX_(PHL)suppressed DR in injured HIBECs and reduced collagen contraction force and the expression of fibrosis biomarkers in LX-2 cells treated with TGF-β.CX_(PHL)suppressed the transcription and transfer of plasminogen activator inhibitor-1(PAI-1)and fibronectin(FN)from the‘DR-like’cholangiocytes to activated HSCs.Mechanistically,the inhibition of PAI-1 and FN by CX_(PHL)was attributed to the untight combination of the acetyltransferase KAT2A and SMAD3,followdd by the suppression of histone 3 lysine 9 acetylation(H3K9ac)-mediated transcription in cholangiocytes.In conclusion,CX_(PHL)exerts stronger anti-cholestatic activity in vivo and in vitro than other CX extracts,and its protective effect on the intracellular communication between cholangiocytes and HSCs is achieved by reducing KAT2A/H3K9ac-mediated transcription and release of PAI-1 and FN.

Statin-induced Liver Injury Patterns: A Clinical Review

Since their introduction in 1987,hydroxymethyl glutaryl coenzyme A reductase(HMG-CoA)inhibitors,more commonly known as statins,have become some of the most widely prescribed medications in the world.Though generally considered to be safe and well tolerated,statins have been associated with several side effects including mild liver dysfunction manifested by increases in aminotransferases.Rarely,statins have been noted to induce more serious hepatic injury,including liver injury with autoimmune features.Current literature supports statin induced liver injury presenting in either hepatocellular or cholestatic patterns,though with the former being the prevailing pattern of injury.Fortunately,severe liver injury is uncommon with statin use and is generally reversible without any intervention other than offending statin cessation.When evaluating cases of suspected statininduced liver injury,a complete medical history,laboratory tests including a complete metabolic panel,autoimmune markers,and viral panel,as well as hepatic imaging,are crucial for a complete causality analysis with validated tools such as Roussel Uclaf Causality Assessment Method.The aim of this review is to review the current evidence for statininduced liver injury and cholestasis.