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
View: Text | PDF
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

×

Figure 4

Hepatic overexpression of S100A11 promotes hepatic cholesterol accumulation and MASH.

Options: View larger image (or click on image) Download as PowerPoint
Hepatic overexpression of S100A11 promotes hepatic cholesterol accumulat...
(A) Schematic diagram of the experimental design using a HFHC diet. (B–E) Plasma levels of TC (B) and LDL-C (C), as well as liver TC (D) and TG (E) levels in S100A11HepKI mice and their littermate controls (S100A11HepROSA) fed a HFHC diet (n = 8–10 per group). (F) Liver H&E staining (top), F4/80 staining (middle), and Picrosirius red staining (bottom) in livers of indicated mice fed a HFHC diet (n = 4). Scale bars: 100 μm. Quantification was shown below. (G) Analysis of FC levels by filipin staining in livers of the indicated mice fed a HFHC diet (n = 3). Scale bar: 10 μm. (H) Western blot analysis of proteins in the SREBP2 pathway in the livers of the indicated mice fed a HFHC diet (n = 4). Quantification was shown below. (I) Representative IHC images of SREBP2 and HMGCR in livers of the indicated mice fed a HFHC diet (n = 4). White scale bars: 50 μm. Graphs show the quantification. MHF, magnified high-power field. (J) Immunofluorescence staining to detect SREBP2 in the nucleus in livers of the indicated mice. Scale bar: 10 μm. (K) Western blot analysis of the inflammation pathway in livers of the indicated mice fed a HFHC diet. For each group, data on 4 individual representative mouse samples are shown (n = 4). Graph shows the quantification. GAPDH was used as an internal control for all Western blot analyses. Data are presented as the mean ± SEM. Data were compared using a 2-tailed, unpaired Student’s t test *, P < 0.05, **P < 0.01, and ***P < 0.001.