Hepatocyte-specific CCAAT/enhancer binding protein α restricts liver fibrosis progression

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Abstract

Metabolic dysfunction–associated steatohepatitis (MASH) — previously described as nonalcoholic steatohepatitis (NASH) — is a major driver of liver fibrosis in humans, while liver fibrosis is a key determinant of all-cause mortality in liver disease independent of MASH occurrence. CCAAT/enhancer binding protein α (CEBPA), as a versatile ligand-independent transcriptional factor, has an important function in myeloid cells, and is under clinical evaluation for cancer therapy. CEBPA is also expressed in hepatocytes and regulates glucolipid homeostasis; however, the role of hepatocyte-specific CEBPA in modulating liver fibrosis progression is largely unknown. Here, hepatic CEBPA expression was found to be decreased during MASH progression both in humans and mice, and hepatic CEBPA mRNA was negatively correlated with MASH fibrosis in the human liver. CebpaΔHep mice had markedly enhanced liver fibrosis induced by a high-fat, high-cholesterol, high-fructose diet or carbon tetrachloride. Temporal and spatial hepatocyte-specific CEBPA loss at the progressive stage of MASH in CebpaΔHep,ERT2 mice functionally promoted liver fibrosis. Mechanistically, hepatocyte CEBPA directly repressed Spp1 transactivation to reduce the secretion of osteopontin, a fibrogenesis inducer of hepatic stellate cells. Forced hepatocyte-specific CEBPA expression reduced MASH-associated liver fibrosis. These results demonstrate an important role for hepatocyte-specific CEBPA in liver fibrosis progression, and may help guide the therapeutic discoveries targeting hepatocyte CEBPA for the treatment of liver fibrosis.

Authors

Tingting Yan, Nana Yan, Yangliu Xia, Vorthon Sawaswong, Xinxin Zhu, Henrique Bregolin Dias, Daisuke Aibara, Shogo Takahashi, Keisuke Hamada, Yoshifumi Saito, Guangming Li, Hui Liu, Hualong Yan, Thomas J. Velenosi, Kristopher W. Krausz, Jing Huang, Shioko Kimura, Yaron Rotman, Aijuan Qu, Haiping Hao, Frank J. Gonzalez