HMN 2025: How Cholesterol buildup in liver fat droplets directly drives fibrosis in metabolic disease, study finds

Cholesterol plays a vital role in the body, providing structural support to cells and serving as a building block for hormone synthesis. However, when cholesterol accumulates or is improperly distributed, it can contribute to the development and progression of disease.

In a new study, published in the Proceedings of the National Academy of Sciences, Yale School of Medicine (YSM) researchers showed that excess cholesterol stored in the liver can directly drive fibrosis in the context of metabolic disease.

Led by Gerald I. Shulman, MD, Ph.D., the study aimed to identify key molecular triggers of metabolic dysfunction–associated steatohepatitis (MASH), a progressive liver disease marked by fat accumulation, inflammation, and fibrosis. According to Shulman, George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology at YSM, understanding the drivers of fibrosis is critical to improving outcomes for patients with MASH.

“Once fibrosis develops, it becomes very difficult to reverse and may ultimately progress to end-stage liver disease,” he says.

Interestingly, says Shulman, it wasn’t the total amount of cholesterol in the liver that mattered most, but rather where it was stored. Specifically, cholesterol accumulated within liver fat droplets emerged as a key driver of liver inflammation and fibrosis.

“It’s not just how much cholesterol is present, it’s about where it ends up,” says Shulman. “In this case, it was the cholesterol in the lipid droplets that triggers the damage. When it comes to lipids and liver disease, it’s all about location.”

The researchers first identified this link using preclinical models and then validated their findings in human liver tissue. They hypothesize that when cholesterol accumulates within liver fat droplets, it may protrude through the droplet coating and trigger an inflammatory response.

“We think that exposed cholesterol triggers intracellular stress pathways, particularly involving lysosomes, that in turn activate hepatic stellate cells and set off a chain reaction that leads to liver inflammation and fibrosis,” says Shulman.

This mechanistic insight offers a possible explanation for how cholesterol drives liver injury and points to new potential therapeutic targets. Shulman and his team are now investigating whether inhibiting the cholesterol synthesis pathway, possibly in combination with other agents, can improve not only liver inflammation and fibrosis but also insulin resistance and fat accumulation in the liver.

“This work gives us new insight into the pathophysiology of MASH,” he says. “We now have the tools and drugs to test this hypothesis, and within the next few years, we hope to design studies that can evaluate these potential therapies more effectively.”