A recent study highlights new insights into the understanding and management of liver fibrosis, a significant issue associated with metabolic fatty liver disease, also referred to as MASLD (metabolic dysfunction-associated steatotic liver disease). The study indicates that activating the PPARβ/δ-AMPK pathway is a promising approach to slow down liver fibrosis progression.
Research spearheaded by Manuel Vázquez Carrera, the head of a group at the Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM) at the University of Barcelona, presents progress in comprehending and treating liver fibrosis. This condition is a critical complication linked to metabolic fatty liver disease, also known as MASLD (metabolic dysfunction-associated steatotic liver disease). The findings suggest that engaging the PPARβ/δ-AMPK pathway is an effective means to delay the advancement of liver fibrosis.
The findings, published in the journal Biomedicine & Pharmacotherapy, were a collaborative effort involving teams led by experts Ángela Maria Valverde from CIBERDEM and Walter Wahli from the University of Lausanne.
The most prevalent chronic liver disease
Metabolic fatty liver disease (MASLD) encompasses a range of liver issues, from merely having fat deposits in the liver to severe liver inflammation, termed metabolic steatohepatitis, which can lead to fibrosis in severe cases. Currently, liver fibrosis serves as a major risk factor for predicting both mortality linked to liver disease and overall mortality rates.
MASLD is a global health concern, as it is the most widespread chronic liver condition, impacting 25% of the global population. Numerous studies indicate a frequent coexistence with type 2 diabetes (DM2). In fact, DM2 can speed up the progression of MASLD, worsening both liver-related and systemic issues. Conversely, MASLD raises the chance of developing DM2 and complicates glucose management in individuals already diagnosed with diabetes.
“In this study, we examined the role of nuclear receptor PPARβ/δ in liver fibrosis development and the activation of hepatic stellate cells, which play a pivotal role in liver fibrosis, in reaction to transforming growth factor β (TGF-β), the primary trigger for fibrosis,” explains Professor Vázquez Carrera, who is affiliated with the UB’s Faculty of Pharmacy and Food Sciences, the UB Institute of Biomedicine (IBUB), and the Sant Joan de Déu Research Institute (IRSJD).
A promising approach to combat liver fibrosis
The findings indicate that a PPARβ/δ agonist (a molecule that activates a specific receptor) aids in preventing glucose intolerance and insulin resistance in peripheral tissues. Furthermore, this agonist halts collagen buildup in the liver and lowers the expression of genes linked to inflammation and fibrosis in mice subjected to a diet that induces liver fibrosis. “Our results imply that activating the PPARβ/δ-AMPK pathway may effectively mitigate liver fibrosis progression,” states Vázquez Carrera.
The research also demonstrates that in hepatic stellate cells, PPARβ/δ activation blocks TGF-β-induced cell migration, a crucial measure of cell activation. Researchers also noticed a reduction in SMAD3 protein phosphorylation and p300 coactivator levels, both vital components in the signaling that promotes fibrosis. “These effects occur due to AMPK activation and ERG1/2 inhibition by PPARβ/δ in hepatic stellate cells,” he concludes.
