Unveiling the role of aldosterone in metabolic dysfunction–associated steatotic liver disease

Fig. 1. Pathophysiological mechanisms in which aldosterone contributes to metabolic dysfunction and indirectly to MASLD. Aldosterone can be stimulated by the renin–angiotensin system or by other factors, including leptin. Leptin, an adipokine secreted by adipose tissue, induces aldosterone synthase expression, resulting in aldosterone excess. Aldosterone excess can act independently through a MR-independent pathway by overactivating GPER, resulting in mitochondrial dysfunction, production of reactive oxygen species, and inflammation. The main mechanism by which aldosterone acts is through binding to the MR in the cytosol of cells expressing MR. Once aldosterone binds to MR, it can act through a rapid non-genomic pathway, producing mitochondrial dysfunction and ROS formation, and stimulating transmembrane receptor EGFR and transmembrane scaffolding protein Caveolin-1, among others. This can further activate a kinase cascade involving c-Src, leading to endothelial dysfunction, particularly in vascular smooth muscle cells. Additionally, it can induce phosphorylation and degradation of IRS-1, which leads to reduced GLUT-4 translocation to the membrane, resulting in hyperglycemia and insulin…

Fig. 2. Proposed direct mechanisms of aldosterone on liver cells. MR activation, through cortisol or aldosterone activation, can drive cell-specific pathological responses in the liver that promote MASLD development and progression. In hepatocytes, MR activation disrupts glucose and lipid metabolism, leading to lipid accumulation, oxidative stress, inflammation, and apoptosis. In liver sinusoidal endothelial cells, MR activation induces endothelial dysfunction, capillarization, increased permeability, leukocyte adhesion, and pro-fibrotic signalling. In Kupffer cells, MR activation promotes a pro-inflammatory phenotype with cytokine release, oxidative stress, and immune cell recruitment, further amplifying inflammation and indirectly activating hepatic stellate cells. In hepatic stellate cells, MR signalling contributes to activation into collagen-producing myofibroblast-like cells, driving fibrosis, although MR-independent effects of aldosterone could be also implicated. Additionally, aldosterone can act through MR-independent pathways, particularly via GPER, which is expressed in hepatocytes and stellate cells and may contribute to liver injury, although its pathological role remains…