S100A11 regulates hepatic cholesterol metabolism and promotes steatohepatitis via noncanonical SREBP2 signaling
Mingfeng Zhan, Xiumei Xu, Huiyin Wu, Qijing Fan, Hongsheng Lu, Chengbin Li, Linqiang Zhang, Tingting Zhu, Yunqian Shen, Jing Liu, Yaomei He, Yingjie Wu, Jingjing Zhang, Xiaoju Zou, Bin Liang
Mingfeng Zhan, Xiumei Xu, Huiyin Wu, Qijing Fan, Hongsheng Lu, Chengbin Li, Linqiang Zhang, Tingting Zhu, Yunqian Shen, Jing Liu, Yaomei He, Yingjie Wu, Jingjing Zhang, Xiaoju Zou, Bin Liang
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Research Article Hepatology Inflammation

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

Abstract

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.

Authors

Mingfeng Zhan, Xiumei Xu, Huiyin Wu, Qijing Fan, Hongsheng Lu, Chengbin Li, Linqiang Zhang, Tingting Zhu, Yunqian Shen, Jing Liu, Yaomei He, Yingjie Wu, Jingjing Zhang, Xiaoju Zou, Bin Liang

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Figure 2

S100A11 can bind to cholesterol.

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S100A11 can bind to cholesterol. (A) The recombinant human S100A11 prote...
(A) The recombinant human S100A11 protein dimer structure (left, Protein Databank [PDB] ID: 2LUC) and its corresponding topological model (right). Light purple and green helices (left) and boxes (right) represent the 5 helical regions of the 2 monomers, respectively. Dark blue and red arrows indicate the 2 β-strands of each monomer. The amino acids shown in red indicate potential cholesterol-binding sites on S100A11. (B) Molecular docking results for S100A11 with cholesterol. The predicted pocket positions of cholesterol interaction with S100A11 amino acid residues are shown. (C) Results for potential sites of S100A11 binding to cholesterol, the corresponding binding energies, and the hydrogen bonding distances. (D) Assay of S100A11 protein binding to the membrane lipid strip. (E) Colocalization of S100A11 with the FC stained by filipin and the ER marker calnexin in Huh7 cells. Scale bars: 10 μm. (F and G) Western blot analysis of S100A11 protein in Huh7 (F) and Hepa1–6 (G) cells treated with cholesterol (Chol), U18666A, or their combination (n = 3). Graphs show the quantification. (H) Schematic diagram of GFP-tagged S100A11 truncations. (I) Western blot analysis of S100A11 point-mutant protein in Huh7 cells treated with cholesterol. (J) Fluorescent expression of GFP-tagged S100A11 point mutations in Huh7 cells treated with cholesterol. Scale bars: 10 μm. (K) Cholesterol binding curves for WT and point mutation S100A11 proteins measured by MST. GAPDH or tubulin was used as an internal control for Western blot analysis. Data are presented as the mean ± SEM. Data were compared using 1-way ANOVA with Dunnett’s test. ***P < 0.001.