The Breakthrough in Understanding and Treating Liver Fibrosis
Liver fibrosis is a serious complication in the context of metabolic fatty liver disease, also known as MASLD (metabolic dysfunction-associated steatotic liver disease). A recent study led by Manuel Vázquez Carrera, a group leader at the Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM) at the University of Barcelona, has revealed significant advances in the understanding and treatment of this condition. The study concludes that the activation of the PPARβ/δ-AMPK pathway can be an effective strategy in slowing the development of liver fibrosis.
The research, published in the journal Biomedicine & Pharmacotherapy, was a collaborative effort between the groups led by experts Ángela Maria Valverde from CIBERDEM and Walter Wahli from the University of Lausanne.
The Global Burden of Metabolic Fatty Liver Disease
MASLD encompasses a spectrum of liver conditions, ranging from simple fat accumulation in the liver to severe inflammation known as metabolic steatohepatitis, which can progress to fibrosis. Liver fibrosis is currently the most significant risk factor for liver disease-related mortality and overall mortality.
This condition is a major global health concern, affecting 25% of the world’s population. Studies have shown that MASLD often coexists with type 2 diabetes (DM2), with the latter accelerating the progression of MASLD by exacerbating hepatic and extrahepatic issues. Conversely, having MASLD increases the risk of developing DM2 and complicates glucose level control in individuals with diabetes.
“In our study, we investigated how the activation of the nuclear receptor PPARβ/δ impacts the development of liver fibrosis and the activation of hepatic stellate cells, which play a crucial role in liver fibrosis in response to transforming growth factor β (TGF-β), the primary stimulus promoting fibrosis,” explains Professor Vázquez Carrera.
A Promising Strategy for Fighting Liver Fibrosis
The findings from the study indicate that a PPARβ/δ agonist can help prevent glucose intolerance and insulin resistance in peripheral tissues. Additionally, this agonist can inhibit collagen accumulation in the liver and suppress the expression of genes associated with inflammation and fibrosis in mice fed a fibrosis-inducing diet. Vázquez Carrera suggests that activating the PPARβ/δ-AMPK pathway may be an effective approach to reducing liver fibrosis development.
Furthermore, the study demonstrated that PPARβ/δ activation in hepatic stellate cells can impede TGF-β-induced cell migration, a significant indicator of cell activation. The researchers observed a reduction in SMAD3 protein phosphorylation and p300 coactivator levels, key components in fibrosis-promoting signaling pathways. Vázquez Carrera concludes that these effects are a result of AMPK activation and ERG1/2 inhibition by PPARβ/δ in hepatic stellate cells.
Overall, the study led by Professor Vázquez Carrera sheds light on the potential of the PPARβ/δ-AMPK pathway as a promising target for combating liver fibrosis, offering new insights into the treatment of this debilitating condition.
