S100A11 regulates hepatic cholesterol metabolism and promotes steatohepatitis via noncanonical SREBP2 signaling.

Dietary cholesterol and de novo cholesterol synthesis in the liver use reciprocal coordination to maintain cholesterol homeostasis. However, high levels of dietary cholesterol still promote excessive cholesterol accumulation in the liver, leading to metabolic dysfunction-associated steatohepatitis (MASH), yet the mechanisms remain poorly understood. Here, we show that hepatic S100 calcium-binding protein A11 (S100A11), a member of the S100 family of calcium-binding proteins, positively responded to dietary cholesterol levels and was involved in hepatic cholesterol metabolism. S100A11 localized to the ER and could bind to cholesterol. In vivo and in vitro, hepatic overexpression of S100A11 led to sterol regulatory element-binding transcription factor 2 (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 triggered the noncanonical entry of SREBP2 into the nucleus through a S100A11/annexin A1/importin β (S100A11/ANXA1/KPNB) axis, distinct from the well-known insulin-induced gene /SREBP cleavage-activating protein or caspase 2 pathways. Therefore, our work identifies S100A11 as a regulator of liver cholesterol metabolism, providing a promising target to treat MASH and hypercholesterolemia.