The role and reversibility of vascular alterations in the development, progression and regression of metabolic dysfunction-associated steatotic liver disease (MASLD)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and can progress from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis and hepatocellular carcinoma. Although portal hypertension has traditionally been viewed as a late consequence of fibrosis, emerging evidence shows that portal pressure and intrahepatic vascular resistance (IHVR) increase already in early MASLD. This thesis investigated hepatic vascular alterations in MASLD, focusing on liver sinusoidal endothelial cell (LSEC) dysfunction, capillarisation and peroxisome proliferator-activated receptor (PPAR)-targeted therapy. Using experimental models and human liver samples, the studies assessed haemodynamics, vascular reactivity, sinusoidal architecture and ultrastructural changes. In an early MASLD model induced by a methionine-choline-deficient diet (MCDD), individual PPAR-α (fenofibrate), PPAR-β/δ (GW501516) and PPAR-γ (roziglitazone) agonists had distinct but partial effects, suggesting that mono-PPAR activation is insufficient to fully correct the vascular phenotype. In contrast, pan-PPAR agonism with lanifibranor normalised portal pressure and IHVR, improved steatosis, reduced α1-adrenergic hyperreactivity, recovered acetylcholine-mediated vasodilation, restored LSEC phenotype and partially corrected sinusoidal architectural distortion. These vascular effects were confirmed in a Zucker fatty rat model fed a high-fat high-fructose diet (HFHFD), representing MASH with obesity, insulin resistance and hypertension. Lanifibranor again normalised portal pressure and IHVR, improved acetylcholine-mediated vasodilation, attenuated vasoconstrictor tone, reduced steatosis and improved systemic arterial pressure. Ultrastructural analyses in experimental and human MASLD further showed that LSEC capillarisation occurs early, progresses across the MASLD spectrum and displays spatial heterogeneity. Lanifibranor restored LSEC fenestrae and porosity, supporting its haemodynamic effects. Overall, this thesis establishes hepatic vascular dysfunction and LSEC capillarisation as early, progressive and reversible drivers of MASLD. Targeting liver vascular biology, particularly through balanced pan-PPAR activation, may therefore represent a promising strategy to improve hepatic haemodynamics, endothelial integrity and MASLD outcomes.