Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid

Abstract

Although the dysregulation of bile acid (BA) composition has been associated with fibrosis progression, its precise roles in liver fibrosis is poorly understood. This study demonstrates that solute carrier family 27 member 5 (SLC27A5), an enzyme involved in BAs metabolism, is substantially downregulated in the liver tissues of patients with cirrhosis and fibrosis mouse models. The downregulation of SLC27A5 depends on RUNX family transcription factor 2 (RUNX2), which serves as a transcriptional repressor. The findings reveal that experimental SLC27A5 knockout (Slc27a5−/−) mice display spontaneous liver fibrosis after 24 months. The loss of SLC27A5 aggravates liver fibrosis induced by carbon tetrachloride (CCI4) and thioacetamide (TAA). Mechanistically, SLC27A5 deficiency results in the accumulation of unconjugated BA, particularly cholic acid (CA), in the liver. This accumulation leads to the activation of hepatic stellate cells (HSCs) by upregulated expression of early growth response protein 3 (EGR3). The re‐expression of hepatic SLC27A5 by an adeno‐associated virus or the reduction of CA levels in the liver using A4250, an apical sodium‐dependent bile acid transporter (ASBT) inhibitor, ameliorates liver fibrosis in Slc27a5−/− mice. In conclusion, SLC27A5 deficiency in mice drives hepatic fibrosis through CA‐induced activation of HSCs, highlighting its significant implications for liver fibrosis treatment.

Whole‐exome sequencing for genetic diagnosis of idiopathic liver injury in children

“… 36 It was recently shown that Slc27a5 deficiency led to spontaneous liver fibrosis development in mice. 37 A homozygous missense mutation (p.His338Tyr) in SLC27A5 has been implicated in Bile acid conjugation defect in a neonate presented with fibrosis and cholestasis in liver biopsy, however there was no experimental evidence provided. 38 The p.Thr308Met was not listed in the ClinVar or previously reported to contribute to a disease susceptibility.…”

Exploring Advanced Therapies for Primary Biliary Cholangitis: Insights from the Gut Microbiota–Bile Acid–Immunity Network

“…CA inhibits the selfrenewal of intestinal stem cells and obstructs the restoration of intestinal epithelial barrier function, exacerbating intestinal inflammatory responses and barrier impairment [50]. In addition, CA accumulation in the liver promotes hepatic stellate cells activation through early growth response protein 3 (EGR3), driving liver fibrosis [51]. Hydrophobic secondary bile acids, such as DCA and LCA, demonstrate immunosuppressive properties by activating G protein-coupled bile acid receptor 1 (GPBAR1, also called TGR5), which suppresses LPS-induced cytokine expression in Kupffer cells, and ameliorating liver inflammation by inhibiting the nuclear factor κB (NF-κB) pathway [52,53].…”