The S100 calcium-binding protein A11 promotes hepatic steatosis through RAGE-mediated AKT-mTOR signaling.

Abstract

RATIONALE:

Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, has become an increasingly severe public health problem. However, the underlying mechanism for the occurrence and development of NAFLD remains largely unknown. S100 calcium-binding protein A11 (S100A11) is a multifunctional protein previously reported to be a poor prognostic indicator of hepatocellular carcinoma, while the role of S100A11 affects NAFLD is still not clear.

METHODS:

Immunohistochemical staining was performed using human NAFLD and control biopsy specimens. Serum level of S100A11 were analyzed by Elisa assays. The S100A11 over-expressed/ knocked-down model was established in vitro or in vivo. The expression levels of genes related to lipid metabolism in liver tissue were performed by quantitative PCR and western blotting. Hepatic lipid accumulation was determined by biochemical measurements and histochemistry.

RESULTS:

We showed that the concentration of serum S100A11 was significantly elevated in NAFLD patients, and expression of S100A11 was remarkedly increased in the livers of NAFLD patients and mouse models. Overexpression of S100A11 in vivo markedly increased liver steatosis, body weight, and serum aspartate aminotransaminase (AST) levels. Mechanistically, our results demonstrated that S100A11 acted as a positive regulator of AKT/mTOR signaling to induce lipid synthesis and aggravate lipid deposition.

CONCLUSIONS:

These results provide evidence for a novel role of S100A11 that contributes to hepatic steatosis, suggesting that targeting S100A11 may be an alternative approach for the treatment of NAFLD.

• Authors: Fei Teng, Jingjing Jiang, Jinhua Zhang, Youwen Yuan, Kangli Li, Bing Zhou, Xuan Zhou, Wenhui Liu, Peizhen Zhang, Deying Liu, Minghua Zheng, Yan Lu, Huijie Zhang
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 117 Pg. 154725 (04 2021) ISSN: 1532-8600 [Electronic] United States
• PMID: 33571540 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• AGER protein, human
• Calcium-Binding Proteins
• Receptor for Advanced Glycation End Products
• S100 Proteins
• S100A11 protein, human
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Adult
• Animals
• Calcium-Binding Proteins (metabolism)
• Carcinoma, Hepatocellular (metabolism)
• Cell Line
• Disease Models, Animal
• Fatty Liver (metabolism)
• Female
• Humans
• Lipid Metabolism (physiology)
• Lipogenesis (physiology)
• Liver (metabolism)
• Liver Neoplasms (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor for Advanced Glycation End Products (metabolism)
• S100 Proteins (metabolism)
• Signal Transduction (physiology)
• TOR Serine-Threonine Kinases (metabolism)