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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/215959
Study of the effects of PPAR-β/δ activators in the treatment of MASH
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[eng] Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease around the world, affecting more than 30% of the global population. MASLD ranges from isolated lipid accumulation or steatosis to its active inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH). MASH is a serious progressive liver disease in which liver inflammation may lead to liver fibrosis and liver dysfunction over time. MASH is often associated with other health problems [e.g. hypertension and type 2 diabetes mellitus (T2DM)] and is a leading cause of liver- related mortality. The increasing burden of MASH on global health systems has created an urgent need to develop effective and safe treatments. In this regard, peroxisome proliferator-activated receptor (PPAR)-β/δ agonists have been proven to be effective in attenuating the progression of MASLD by ameliorating insulin resistance (IR), reducing lipogenesis, and alleviating inflammation and endoplasmic reticulum (ER) stress. However, the role of PPAR-β/δ in hepatic fibrosis remains controversial. In the present thesis, we show that two PPAR-β/δ agonists, elafibranor and GW501516, prevented glucose intolerance and IR and reduced collagen accumulation in the liver of MASH mice. Surprisingly, elafibranor, a dual PPAR-α/-β/δ agonist, increased the levels of the EMT-promoting protein S100A4 via PPAR-β/δ activation, as confirmed in liver cells. Additionally, it decreased the levels of ASB2, a protein promoting S100A4 degradation. Conversely, GW501516, a specific PPAR-β/δ ligand, inhibited TGF-β1-induced HSC activation by reducing the suppressor of mothers against decapentaplegic (SMAD)3, as well as the levels of the SMAD3 co-activator p300 via AMP-activated protein kinase (AMPK) activation and the subsequent inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2). Overall, these findings reveal novel mechanisms underlying the therapeutic effects of PPAR-β/δ agonists in liver diseases.
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ZHANG, Meijian. Study of the effects of PPAR-β/δ activators in the treatment of MASH. [consulta: 3 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/215959]