bims-liverm 2023-08-20 papers

Issue of 2023–08–20
three papers selected by

Curr Protein Pept Sci. 2023 Aug 18.

Bile acids as signaling molecules: Role of ursodeoxycholic acid in cholestatic liver disease.

Eduardo Cifuentes-Silva, Claudio Cabello-Verrugio.

Ursodeoxycholic acid (UDCA) is a natural substance physiologically produced in the liver. Initially used to dissolve gallstones, it is now successfully used in treating primary biliary cirrhosis and as adjuvant therapy for various hepatobiliary cholestatic diseases. However, the mechanisms underlying its beneficial effects are not entirely clear. Evidence suggests three mechanisms of action for UDCA that could benefit humans with cholestatic liver disease (CLD): protection of cholangiocytes against hydrophobic bile acid (BA) cytotoxicity, stimulation of hepatobiliary excretion, and protection of hepatocytes against BA-induced apoptosis. These mechanisms may act individually or together to potentiate them. At the molecular level, it has been observed that UDCA can generate modifications in the transcription and translation of proteins essential in the transport of BA, correcting the deficit in BA secretion in CLD, in addition to activating signaling pathways to translocate these transporters to the sites where they should fulfill their function. Inhibition of BA-induced hepatocyte apoptosis may play a role in CLD, characterized by BA retention in the hepatocyte. Thus, different mechanisms of action contribute to the improvement after UDCA administration in CLD. On the other hand, the effects of UDCA on tissues that possess receptors that may interact with BAs in pathological contexts, such as skeletal muscle, are still unclear. The objective of this work seeks to describe the main molecular mechanisms by which UDCA acts in the human body, emphasizing the interaction in other tissues than the liver.

Keywords: Ursodeoxycholic acid; bile acids; cholestasis; liver diseases; signaling; skeletal muscle

DOI: https://doi.org/10.2174/1389203724666230818092800

Cell Mol Gastroenterol Hepatol. 2023 Aug 12. pii: S2352-345X(23)00150-9. [Epub ahead of print]

Inhibiting Wnt signaling reduces cholestatic injury by disrupting the inflammatory axis.

Mary Ayers, Karis Kosar, Yuhua Xue, Chhavi Goel, Matthew Carson, Elizabeth Lee, Silvia Liu, Eva Brooks, Pamela Cornuet, Michael Oertel, Bharat Bhushan, Kari Nejak-Bowen.

BACKGROUND & AIMS: β-catenin, the effector molecule of the Wnt signaling pathway, has been shown to play a crucial role in bile acid homeostasis through direct inhibition of farnesoid X receptor (FXR), which has pleiotropic effects on bile acid homeostasis. We hypothesize that simultaneous suppression of β-catenin signaling and activation of FXR in a mouse model of cholestasis will reduce injury and biliary fibrosis through inhibition of bile acid synthesis.
METHODS: To induce cholestasis, we performed bile duct ligation on wild-type male mice. Eight hours after surgery, mice received FXR agonists obeticholic acid, tropifexor, or GW-4064, or Wnt inhibitor Wnt-C59. Severity of cholestatic liver disease and expression of target genes was evaluated after either 5 days or 12 days of treatment.
RESULTS: We found that while the FXR agonists worsened BDL-induced injury and necrosis after 5 days, Wnt-C59 did not. After 12 days of BDL, Wnt-C59 treatment, but not GW-4064 treatment, reduced both the number of infarcts and the number of inflammatory cells in liver. RNA-seq analysis of whole livers revealed a notable suppression of NF-κB signaling when Wnt signaling is inhibited. We then analyzed transcriptomic data to identify a cholangiocyte-specific signature in our model and demonstrated that Wnt-C59-treated livers were enriched for genes expressed in quiescent cholangiocytes, whereas genes expressed in activated cholangiocytes were enriched in BDL alone. A similar decrease in biliary injury and inflammation occurred in Mdr2 KO mice treated with Wnt-C59.
CONCLUSIONS: Inhibiting Wnt signaling suppresses cholangiocyte activation and disrupts the NF-κB-dependent inflammatory axis, reducing cholestatic-induced injury.

Keywords: bile acids; cholangiocytes; farnesoid X receptor; β-catenin, NF-κB

DOI: https://doi.org/10.1016/j.jcmgh.2023.08.004

J Endocrinol. 2023 09 01. pii: e230119. [Epub ahead of print]258(3):

BRD7 improves glucose homeostasis independent of IRS proteins.

Yoo Kim, Junsik M Lee, Youngah Han, Rongya Tao, Morris F White, Renyan Liu, Sang Won Park.

Bromodomain-containing protein 7 (BRD7) has emerged as a player in the regulation of glucose homeostasis. Hepatic BRD7 levels are decreased in obese mice, and the reinstatement of hepatic BRD7 in obese mice has been shown to establish euglycemia and improve glucose homeostasis. Of note, the upregulation of hepatic BRD7 levels activates the AKT cascade in response to insulin without enhancing the sensitivity of the insulin receptor (InsR)-insulin receptor substrate (IRS) axis. In this report, we provide evidence for the existence of an alternative insulin signaling pathway that operates independently of IRS proteins and demonstrate the involvement of BRD7 in this pathway. To investigate the involvement of BRD7 as a downstream component of InsR, we utilized liver-specific InsR knockout mice. Additionally, we employed liver-specific IRS1/2 knockout mice to examine the requirement of IRS1/2 for the action of BRD7. Our investigation of glucose metabolism parameters and insulin signaling unveiled the significance of InsR activation in mediating BRD7's effect on glucose homeostasis in the liver. Moreover, we identified an interaction between BRD7 and InsR. Notably, our findings indicate that IRS1/2 is not necessary for BRD7's regulation of glucose metabolism, particularly in the context of obesity. The upregulation of hepatic BRD7 significantly reduces blood glucose levels and restores glucose homeostasis in high-fat diet-challenged liver-specific IRS1/2 knockout mice. These findings highlight the presence of an alternative insulin signaling pathway that operates independently of IRS1/2 and offer novel insights into the mechanisms of a previously unknown insulin signaling in obesity.

Keywords: BRD7; glucose metabolism; insulin receptor signaling; insulin receptor substrates

DOI: https://doi.org/10.1530/JOE-23-0119