Shi Su, PhD

Travel Award
$1,500

Brigham and Women's Hospital

ATP-Citrate Lyase in Hepatic Stellate Cells Promotes Liver Fibrosis in Response to Chemical Injury

Mentor: David Cohen, MD, PhD

Chronic liver disease leads to scarring and stiffening of the liver, a condition called liver fibrosis. When the liver is injured, hepatic stellate cells (HSCs) in the liver are responsible for initiating the process of liver fibrosis in an attempt to repair the damage. When there is ongoing liver damage, this process becomes maladaptive and can lead to cirrhosis. For the HSCs to initiate liver fibrosis, they need to be activated. Our study tries to understand whether blocking an enzyme named ATP-citrate lyase (ACLY) that sustains the nutrients and factors required for the normal functions of HSCs could attenuate the process of liver stiffening after liver injury. We previously showed in human HSCs that inhibiting ACLY reduced not only HSC metabolism in their non-activated state, but also HSC activation in response to TGFβ, a signaling molecule that activates HSCs. Next, we aimed to evaluate whether ACLY level in HSCs promotes liver fibrosis in response to chemical injury. We developed a mouse model that lacks ACLY in the HSCs. The HSCs in these mice showed reduced levels of proteins that are important for HSC activation. We also injected a chemical toxin called carbon tetrachloride to induce chemical injury in mice. Normal mice developed liver fibrosis and increased ACLY level after 4 weeks of chemical injury. However, mice lacking ACLY in their HSCs showed reduced liver fibrosis and reduced levels of proteins that are associated with HSC activation compared to normal mice. By identifying the pathways and factors that are regulated by ACLY in the HSCs in response to liver injury, we hope to use the findings of our study to help developing drugs for the management of liver fibrosis in patients.