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Bile components play a critical role in maintaining gut microbiota homeostasis. In cholestasis, bile secretion is impaired, leading to liver injury. However, it remains to be elucidated whether gut microbiota plays a role in cholestatic liver injury. Here, we performed a sham operation and bile duct ligation (BDL) in antibiotic-induced microbiome depleted (AIMD) mice and assessed liver injury and fecal microbiota composition in these mice. Significant reductions in gut microbiota richness and diversity were found in AIMD-sham mice when compared to sham controls. Three-day BDL leads to great elevation of plasma ALT, ALP, total bile acids, and bilirubin where reduced diversity of the gut microbiota was also found. AIMD further aggravated cholestatic liver injury evidenced by significantly higher levels of plasma ALT and ALP, associated with further reduced diversity and increased Gram-negative bacteria in gut microbiota. Further analyses revealed increased levels of LPS in the plasma of AIMD-BDL mice where elevated expression of inflammatory genes and decreased expression of hepatic detoxification enzymes were also found in liver when compared to the BDL group. These findings indicate that gut microbiota plays a critical role in cholestatic liver injury. Maintaining its homeostasis may alleviate liver injury in patients with cholestasis. [ABSTRACT FROM AUTHOR]

Semaphorin 7A (SEMA7A) is a membrane‐bound protein that involves axon growth and other biological processes. SEMA7A mutations are associated with vertebral fracture and Kallmann syndrome. Here, we report a case with a mutation in SEMA7A that displays familial cholestasis. WGS reveals a SEMA7AR148W homozygous mutation in a female child with elevated levels of serum ALT, AST, and total bile acid (TBA) of unknown etiology. This patient also carried a SLC10A1S267F allele, but Slc10a1S267F homozygous mice exhibited normal liver function. Similar to the child, Sema7aR145W homozygous mice displayed elevated levels of serum ALT, AST, and TBA. Remarkably, liver histology and LC‐MS/MS analyses exhibited hepatocyte hydropic degeneration and increased liver bile acid (BA) levels in Sema7aR145W homozygous mice. Further mechanistic studies demonstrated that Sema7aR145W mutation reduced the expression of canalicular membrane BA transporters, bile salt export pump (Bsep), and multidrug resistance‐associated protein‐2 (Mrp2), causing intrahepatic cholestasis in mice. Administration with ursodeoxycholic acid and a dietary supplement glutathione improved liver function in the child. Therefore, Sema7aR145W homozygous mutation causes intrahepatic cholestasis by reducing hepatic Bsep and Mrp2 expression. SYNOPSIS: A new type of progressive familial intrahepatic cholestasis (PFIC) was caused by the homozygous R148W mutation in SEMA7A. Preliminary mechanistic studies revealed that the mutation reduced hepatic expression of canalicular membrane bile acid (BA) efflux transporters Bsep and Mrp2, resulting in intrahepatic cholestasis. A female child patient presented with elevated levels of serum ALT, AST, and total bile acid (TBA) of unknown etiology.A SEMA7AR148W homozygous mutation was identified in the child patient.The Sema7aR145W (human R148W) homozygous mice displayed elevated levels of serum ALT, AST, and TBA, as well as hepatocyte hydropic degeneration and intrahepatic accumulation of conjugated BAs.The Sema7aR145W homozygous mutation reduced the expression of canalicular membrane Bsep and Mrp2 in mouse livers and sandwich‐cultured primary hepatocytes.Administration with ursodeoxycholic acid (UDCA) and a dietary supplement glutathione (GSH) were effective for this new type of PFIC. [ABSTRACT FROM AUTHOR]

The progression of cholestasis is characterized by excessive accumulation of bile acids (BAs) in the liver, which leads to oxidative stress (OS), inflammation and liver injury. There are currently limited treatments for cholestasis. Therefore, appropriate drugs for cholestasis treatment need to be developed. Dimethyl fumarate (DMF) has been widely used in the treatment of various diseases and exerts antioxidant and anti-inflammatory effects, but its effect on cholestatic liver disease remains unclarified. We fed mice 3,5-diethoxycarbonyl-1,4-dihydrocollidine or cholic acid to induce cholestatic liver injury and treated these mice with DMF to evaluate its protective ability. Alanine aminotransferase, aspartate aminotransferase, and total liver BAs were assessed as indicators of liver function. The levels of OS, liver inflammation, transporters and metabolic enzymes were also measured. DMF markedly altered the relative ALT and AST levels and enhanced the liver antioxidant capacity. DMF regulated the MST/NRF2 signaling pathway to protect against OS and reduced liver inflammation through the NLRP3/GSDMD signaling pathway. DMF also regulated the levels of BA transporters by promoting FXR protein expression. These findings provide new strategies for the treatment of cholestatic liver disorders. • Dimethyl fumarate reverses the increases in serum ALT and AST induced by 3,5-diethoxycarbonyl-1,4-dihydroxychollidine or cholic acid, and improves the antioxidant capacity of mice. • Dimethyl fumarate activates the MST-NRF2 pathway and thus inhibits oxidative stress. • Dimethyl fumarate activates FXR to regulate bile acid transporters. • Dimethyl fumarate suppresses the NLRP3/GSDMD pathway and thereby ameliorates hepatic inflammation. [ABSTRACT FROM AUTHOR]

[Display omitted] • HA-PEI actively targets the liver through the CD44 receptor to reduce the off-target effects of PEI (highest effect at 1000 K). • This study provided a therapeutic agent for late-stage liver injury induced by acetaminophen that outperforms the FDA-approved drug N-acetylcysteine. • HA-PEI could increase oxygen content, eliminate ROS, and maintain mitochondrial membrane potential to protect hepatocytes that are under oxidative stress and inhibit the secretion of inflammatory factors to block the migration of immune cells to the liver, safeguarding hepatocytes from secondary damage. Acute liver injury (ALI) is one of the most important causes of liver failure, and there are no FDA-approved drugs that could therapy late-stage ALI. It has been shown in this study that HA-PEI, a molecule formed by covalently combining HA and PEI, can effectively treat advanced ALI. Through the CD44 receptor, HA-PEI could target the liver actively, with the highest liver-targeting effect confirmed at 1000 K. The underlying mechanism of protection of HA-PEI is by increasing oxygen content, reducing ROS, and maintaining mitochondrial membrane potential. HA-PEI also inhibits the secretion of inflammatory factors and blocks the migration of immune cells to the liver, protecting the hepatocytes not suffer from secondary damage. More importantly, for late-stage ALI, NAC, as the only FDA-approved drug, is completely ineffective, whereas HA-PEI has an excellent therapeutic effect. This work provides a new safe therapeutic agent for ALI, which has a bright application prospect. [ABSTRACT FROM AUTHOR]