Canonical Wnt signaling promotes HSC glycolysis and liver fibrosis through an LDH-A/HIF-1α transcriptional complex

Abstract

Background and Aims: Aerobic glycolysis reprogramming occurs during HSC activation, but how it is initiated and sustained remains unknown. We investigated the mechanisms by which canonical Wnt signaling regulated HSC glycolysis and the therapeutic implication for liver fibrosis. Approach and Results: Glycolysis was examined in HSC-LX2 cells upon manipulation of Wnt/β-catenin signaling. Nuclear translocation of lactate dehydrogenase A (LDH-A) and its interaction with hypoxia-inducible factor-1α (HIF-1α) were investigated using molecular simulation and site-directed mutation assays. The pharmacological relevance of molecular discoveries was intensified in primary cultures, rodent models, and human samples. HSC glycolysis was enhanced by Wnt3a but reduced by β-catenin inhibitor or small interfering RNA. Wnt3a-induced rapid transactivation and high expression of LDH-A dependent on TCF4. Wnt/β-catenin signaling also stimulated LDH-A nuclear translocation through importin β2 interplay with a noncanonical nuclear location signal of LDH-A. Mechanically, LDH-A bound to HIF-1α and enhanced its stability by obstructing hydroxylation-mediated proteasome degradation, leading to increased transactivation of glycolytic genes. The Gly28 residue of LDH-A was identified to be responsible for the formation of the LDH-A/HIF-1α transcription complex and stabilization of HIF-1α. Furthermore, LDH-A-mediated glycolysis was required for HSC activation in the presence of Wnt3a. Results in vivo showed that HSC activation and liver fibrosis were alleviated by HSC-specific knockdown of LDH-A in mice. β-catenin inhibitor XAV-939 mitigated HSC activation and liver fibrosis, which were abrogated by HSC-specific LDH-A overexpression in fibrotic mice. Conclusions: Inhibition of HSC glycolysis by targeting Wnt/β-catenin signaling and LDH-A had therapeutic promise for liver fibrosis.

Role of lactate and lactate metabolism in liver diseases (Review)

“…The Wnt/β-catenin signaling pathway enhances LDHA stability, promoting glycolysis and liver fibrosis. In mice, the specific deletion of LDHA in HSCs alleviates liver fibrosis ( 146 ). Therefore, the inhibition of LDHA may be an effective treatment for liver fibrosis.…”

Inhibition of tartrate-resistant acid phosphatase 5 can prevent cardiac fibrosis after myocardial infarction

“…In recent years, studies have shown that the Wnt signaling pathway plays an integral role in the fibrosis in multiple organs(Seo et al 2019 ; Yiu et al 2021 ; Wang et al 2024 ). Glycogen synthase kinase-3β (GSK3β) is a key regulatory factor in the Wnt/β-catenin signaling pathway that maintains the balance between cytoplasmic degradation and nuclear translocation of β-catenin (Guo et al 2017 ).…”

Deletion of GPR81 activates CREB/Smad7 pathway and alleviates liver fibrosis in mice

“…A growing body of evidence suggests that metabolic reprogramming is a critical pathological event driving the progression of various disorders, including liver fibrosis, a common consequence of chronic hepatic disorders(Gilgenkrantz et al 2021 ; Trivedi et al 2021 ). Enhanced glycolysis has been regarded as a typical feature of liver fibrosis(Wang et al 2024 ), while inhibition of glycolysis results in beneficial outcomes in experimental animals with liver fibrosis(Xiang et al 2023 ; Li et al 2023 ). However, the molecular mechanisms underlying the detrimental significance of glycolysis in fibrogenesis have not been fully understood.…”