Hormonal and metabolic imbalance accelerates liver fibrosis
The liver can suffer profound damage when metabolism and hormones no longer function in harmony. An abnormal accumulation of fat in this organ, often linked to poor management of sugars and lipids by the body, triggers a chain reaction leading to persistent inflammation and then excessive scarring known as fibrosis. This process, which affects millions of people, originates from systemic disorders where adipose tissue, hormones such as insulin and glucagon, and inflammatory signals play a key role.
Adipose tissue, especially when located around internal organs, releases excess fatty acids when its storage capacity is exceeded. These fats, transported to the liver, accumulate there and disrupt its function. They activate inflammatory signaling pathways in liver cells, attracting immune cells such as macrophages. In response to the lipid overload, these release substances that worsen inflammation and activate the liver’s stellate cells, which are responsible for producing scar tissue. Over time, this fibrosis can progress to serious complications such as cirrhosis or cancer.
Hormones that regulate metabolism, particularly insulin and glucagon, see their balance disrupted. Insulin resistance, where cells respond less effectively to this hormone, forces the pancreas to produce more. This promotes fat production in the liver and reduces its ability to eliminate excess sugar. Glucagon, on the other hand, maintains its normal action on sugar production but has its effect on amino acid metabolism disrupted. Together, these hormonal imbalances amplify cellular stress and accelerate disease progression.
Mitochondria, the cell’s energy powerhouses, also experience dysfunction. Initially, they attempt to adapt by burning more fat, but as the disease worsens, their capacity diminishes. This leads to an accumulation of toxic products, increased oxidative stress, and a decrease in metabolic flexibility—that is, the liver’s ability to efficiently switch from one energy source to another as needed.
Differences between men and women also play a role. Sex hormones, such as estrogen and testosterone, influence fat distribution and insulin sensitivity. Premenopausal women benefit from better protection due to a more favorable fat distribution and higher levels of adiponectin, a hormone with anti-inflammatory effects. After menopause, the drop in estrogen reduces this protection, increasing the risk of liver complications. In men, a testosterone deficiency or an excess of male hormones can also worsen the disease.
The gut also participates in this vicious cycle. An imbalance in its bacterial flora, called dysbiosis, increases the permeability of its wall, allowing pro-inflammatory substances to reach the liver. These molecules activate liver immune cells, amplifying inflammation and fibrosis. Bile acids, produced by the liver and modified by gut bacteria, also influence fat and sugar metabolism. Their imbalance worsens liver disorders.
Emerging treatments target these mechanisms. Some drugs act on nuclear receptors such as PPARs, improving insulin sensitivity and reducing inflammation. Others, like GLP-1 analogs, help regulate blood sugar and weight, indirectly mitigating liver damage. Thyroid hormones, by stimulating fat oxidation and reducing their synthesis, also offer a promising therapeutic avenue. Finally, fibroblast growth factors, such as FGF21, act on multiple fronts: reducing inflammation, improving metabolism, and limiting fibrosis.
These advances highlight the importance of a holistic approach, taking into account the complex interactions between organs, hormones, and metabolism. By restoring the balance of these systems, it becomes possible to slow down, or even reverse, liver damage and improve patient health.
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Original Publication
DOI: https://doi.org/10.1007/s00125-026-06774-7
Title: Metabolic drivers of MASLD and MASH: from hormonal imbalance to fibrosis
Journal: Diabetologia
Publisher: Springer Science and Business Media LLC
Authors: Amalia Gastaldelli; Egeria Scoditti; Maria Paula Macedo