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 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, PhD, 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.”
Other Yale authors of the study include Ikki Sakuma, Rafael Gaspar, Ali Nasiri, Sylvie Dufour, Mario Kahn, Jie Zheng, Traci LaMoia, Mateus Guerra, Dean Yimlamai, Daniel Vatner, Kitt Falk Petersen, and Varman Samuel.
The research reported in this news article was supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (awards F31DK126362, T32GM007324, P30DK34989, R01DK119968, R01DK113984, P30DK045735, and R01DK133143) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the Manpei Suzuki Diabetes Foundation, Mishima Kaiun Memorial Foundation, Kowa Life Science Foundation, Japan Foundation for Applied Enzymology, Takeda Science Foundation, Ono Medical Research Foundation, and Japan’s Ministry of Education, Culture, Sports, Science, and Technology.
Endocrinology and Metabolism, one of 10 sections in the Yale Department of Internal Medicine, improves the health of individuals with endocrine and metabolic diseases by advancing scientific knowledge, applying new information to patient care, and training the next generation of physicians and scientists to become leaders in the field. To learn more, visit Endocrinology and Metabolism.