S100A11 regulates hepatic cholesterol metabolism and promotes steatohepatitis via non-canonical SREBP2 signaling

Dietary cholesterol and de novo cholesterol synthesis in the liver use reciprocal coordination to maintain cholesterol homeostasis. However, high level of dietary cholesterol still promotes excessive cholesterol accumulation in the liver, leading to metabolic dysfunction-associated steatohepatitis (MASH), yet the mechanisms remain poorly understood. Here we show that hepatic S100A11, a member of the S100 family of calcium-binding proteins, positively responds to the dietary cholesterol level and is involved in hepatic cholesterol metabolism. S100A11 localizes to the endoplasmic reticulum and can bind to cholesterol. In vivo and in vitro, hepatic overexpression of S100A11 led to SREBP2 activation to promote cholesterol synthesis, uptake, and accumulation, consequently exacerbating steatohepatitis. In contrast, inactivation of S100A11 had opposite effects and improved steatohepatitis. Mechanistically, S100A11 triggers the non-canonical entry of SREBP2 into the nucleus through a S100A11-ANXA1-KPNB axis, distinct from the well-known INSIG-SCAP pathway or Caspase2 pathways. Therefore, our work identifies S100A11 as a regulator of liver cholesterol metabolism, providing a promising target to treat MASH and hypercholesterolemia.