Activation of PPARβ/δ-AMPK pathway shown to slow liver fibrosis development

A study led by Manuel Vázquez Carrera, group leader at the Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM) at the University of Barcelona, reveals advances in the understanding and treatment of liver fibrosis, a serious complication in the context of metabolic fatty liver disease, also known as MASLD (metabolic dysfunction-associated steatotic liver disease). This study concludes that activation of the PPARβ/δ-AMPK pathway is an effective strategy to slow the development of liver fibrosis.

The paper, published in the journal Biomedicine & Pharmacotherapy, also involved the collaboration of the groups led by experts ángela Maria Valverde, from CIBERDEM, and Walter Wahli, from the University of Lausanne.

The most common chronic liver disease

Metabolic fatty liver disease (MASLD) integrates a set of liver conditions ranging from simple isolated fat deposition in the liver to severe inflammation of the organ known as metabolic steatohepatitis, which in some cases can progress to fibrosis. For now, liver fibrosis is the most relevant risk factor for predicting both liver disease-related mortality and overall mortality.

MASLD is a global health issue, as it is the most common chronic liver disease, affecting 25% of the world's population. Numerous studies have shown that this condition often coexists with type 2 diabetes (DM2). In fact, DM2 can accelerate the progression of MASLD by aggravating both hepatic and extrahepatic problems. In turn, having MASLD increases the risk of developing DM2 and complicates the control of glucose levels in people who already have diabetes.

In this study we analyzed how the activation of the nuclear receptor PPARβ/δ influences the development of liver fibrosis and the activation of hepatic stellate cells, which are mainly responsible for fibrosis in the liver, in response to transforming growth factor β (TGF-β), the main stimulus that promotes fibrosis."

Professor Vázquez Carrera, UB's Faculty of Pharmacy and Food Sciences, UB Institute of Biomedicine (IBUB) and Sant Joan de Déu Research Institute (IRSJD)

An effective strategy for tackling liver fibrosis

The results reveal that a PPARβ/δ agonist (a compound that binds to and activates a specific receptor) helps prevent glucose intolerance and insulin resistance in peripheral tissues. In addition, this agonist prevents collagen accumulation in the liver and reduces the expression of genes related to inflammation and fibrosis in mice that were fed a diet designed to induce liver fibrosis. "Our findings suggest that activating the PPARβ/δ-AMPK pathway could be an effective strategy to reduce the development of liver fibrosis", says Vázquez Carrera.

The study also revealed that in hepatic stellate cells, PPARβ/δ activation inhibits TGF-β-induced cell migration, which is a key indicator of cell activation. In addition, researchers observed a decrease in SMAD3 protein phosphorylation and p300 coactivator levels, both crucial elements in fibrosis-promoting signalling. "These effects are due to activation of AMPK and inhibition of ERG1/2 by PPARβ/δ in hepatic stellate cells", he concludes.