Inhibition of Cholesterol Synthesis in T Cells Protects the Liver Against Steatosis, Inflammation, and Oxidative Stress in Metabolic Dysfunction-Associated Steatohepatitis

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a manifestation of systemic metabolic disease defined by abnormal lipid metabolism and causes liver disease. Inflammation driven by immune cells has been linked to liver damage, fibrosis, and the progression of MASH. Here, single-cell transcriptome analysis disclosed the increasing hepatic infiltration of CD8⁺ T cells in a murine methionine- and choline-deficient (MCD) diet-induced MASH model. Simvastatin alleviated the progression of MCD-diet-induced MASH, accompanied by the decreased infiltration of T cells. Depletion of CD8⁺ T cells also improved MASH progression. It is widely recognized that cholesterol plays an indispensable role in tuning the activation and function of CD8⁺ T cells. We found that specific inhibition of cholesterol synthesis in T cells significantly reduced MCD-induced hepatic steatosis, damage, inflammation, and concurrently lowered the accumulation of T cells and macrophages in the liver. Mechanistic studies revealed that MCD-induced hepatic oxidative stress was reduced by inhibiting T-cell cholesterol metabolism. Simvastatin ameliorated MASH in mice, at least in part through inhibiting the infiltration and effector function of CD8⁺ T cells. Collectively, our findings provide compelling evidence that pharmacological modulation of T-cell cholesterol metabolism may represent a promising therapeutic approach in the treatment of MASH.