Why Does Liver Stiffness Worsen Disease? Seoul National University Team Finds the Answer [Reading Science]

Molecular Mechanism Identified: Increased Liver Tissue Stiffness Induces Cholesterol Accumulation in Hepatocytes
Published in 'Advanced Science': Clues for New Treatment Strategies in Metabolic Dysfunction-Associated Steatotic Liver Disease

Research has shown that liver fibrosis, which causes the liver to become stiff, is not merely an indicator of disease progression, but can directly disrupt the metabolic functions of hepatocytes and worsen the disease.

On March 9, a research team led by Dr. Na-Young Lee (first author) and Professor Ja-Hyun Goo of the College of Pharmacy at Seoul National University, in collaboration with Professor Won Kim of Boramae Medical Center, Seoul National University College of Medicine, announced that they have identified the molecular mechanism by which increased liver tissue stiffness induces cholesterol accumulation within hepatocytes in metabolic dysfunction-associated steatotic liver disease (MASLD).

Schematic diagram of the mechanism of hepatocyte cholesterol accumulation according to liver tissue stiffness. In the normal liver, YAP/TAZ remains inactive outside the nucleus, and the LXRα-RXRα complex functions to maintain cholesterol efflux (left). In contrast, when tissue stiffness increases due to liver fibrosis, YAP/TAZ is activated and translocates into the nucleus, inhibiting LXRα function and resulting in cholesterol accumulation within hepatocytes (right). Provided by the research team

Liver 'Stiffness' Directly Disrupts Hepatocyte Metabolic Function

Liver fibrosis is a key progression stage in chronic liver disease, and as fibrosis becomes more severe, the risk of liver function deterioration and complications increases significantly. Clinically, liver stiffness, which refers to the 'hardness' of liver tissue, is measured to assess the severity and prognosis of fibrosis.

However, until now, it has not been clearly revealed how the physical environmental change of increasing liver tissue stiffness affects hepatocyte function.

To clarify this, the research team conducted a multilayered study integrating data from cells, animals, and patients. In their cell experiments, they used a hydrogel culture system that precisely controls substrate stiffness, culturing hepatocytes in both soft and stiff substrate environments. As a result, they observed that in a stiff environment, hepatocytes sense mechanical stimuli, leading to changes in metabolic programming and increased intracellular cholesterol accumulation.

Cholesterol Accumulation via the YAP/TAZ-LXRα Pathway

The research team also elucidated the molecular mechanism underlying these phenomena. In hepatocytes exposed to a stiff substrate environment, the YAP/TAZ transcription factors (mechanotransduction proteins that sense physical stimuli in cells) become activated and translocate into the nucleus. During this process, the function of the nuclear receptor LXRα (which regulates cholesterol metabolism) is suppressed.

When YAP/TAZ is activated, LXRα fails to adequately induce the expression of genes related to cholesterol efflux, shifting the metabolic balance toward cholesterol accumulation within hepatocytes. Through this, the research team proposed a disease progression pathway: increased tissue stiffness → activation of YAP/TAZ → impaired LXRα function → cholesterol accumulation.

Additionally, analysis of tissue data from a mouse model with hepatocyte-specific gene deletion and from 229 patients with metabolic dysfunction-associated steatotic liver disease found that higher liver stiffness correlated with a tendency for decreased expression of genes involved in cholesterol efflux. This suggests that increased tissue stiffness can exacerbate metabolic dysfunction in hepatocytes, creating a vicious cycle that worsens the disease.

The researchers emphasized the significance of this study, noting that it reinterprets liver stiffness not simply as a diagnostic indicator, but as a pathogenic factor driving disease progression.

Professor Ja-Hyun Goo of the College of Pharmacy at Seoul National University stated, "We have demonstrated that changes in the physical environment of liver tissue can directly disrupt the metabolic function of hepatocytes," adding, "We expect this will provide important clues for discovering new therapeutic targets for treating metabolic dysfunction-associated steatotic liver disease and liver fibrosis."

This study was supported by the Excellent Young Researcher and Pioneer Research programs of the Ministry of Science and ICT, and was published online on February 26 in the international journal 'Advanced Science' (IF 14.1).

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