Hepatocyte-specific CCAAT/enhancer binding protein α restricts liver fibrosis progression
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
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
View: Text | PDF
Research Article Hepatology

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

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

×

Figure 6

Hepatocyte CEBPA deficiency–induced Spp1 expression and OPN release activates HSCs to promote MASH fibrosis.

Options: View larger image (or click on image) Download as PowerPoint
Hepatocyte CEBPA deficiency–induced Spp1 expression and OPN release acti...
(A) Fibrosis gene mRNAs of primary HSCs treated with supernatants from hepatocytes or with mouse OPN antibody (OPN Ab), n = 4. shCtrl, control scrambled shRNA; shSpp1, Spp1 shRNA. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with WT+shCtrl, while *P < 0.05, **P < 0.01, ***P < 0.001 compared with KO+shCtrl. (B–F) Liver Cebpa and Spp1 mRNAs (B, n = 9), serum OPN (C, n = 9), representative histological staining (D), quantitation of Sirius red staining (E, n = 9), and liver mRNAs in fibrosis and inflammation (F, n = 9) in 16-week HFCFD-fed CebpaΔHep mice treated with AAV8-control scrambled shRNA (control) or AAV8-Spp1 shRNA (shSpp1). (G–K) Liver Cebpa and Spp1 mRNAs (G, n = 6), serum OPN (H, n = 6), representative histological staining (I), quantitation of Sirius red staining (J, n = 6) and liver mRNAs in fibrosis and inflammation (K, n = 6) in CebpaΔHep,ERT2 mice fed a HFCFD for 24 weeks and treated with tamoxifen for the last 12 weeks with AAV8 dosing at 1 week prior to tamoxifen dosing. Data represent mean ± SEM. Cebpafl/fl Control or shSpp1, Cebpafl/fl mice treated with AAV8-control scrambled shRNA or AAV8-shSpp1. CebpaΔHep or CebpaΔHep,ERT2 Control or shSpp1, CebpaΔHep or CebpaΔHep,ERT2 mice treated with AAV8-control scrambled shRNA or AAV8-shSpp1. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with Cebpafl/fl Control, while *P < 0.05, **P < 0.01, ***P < 0.001 compared with CebpaΔHep Control or CebpaΔHep,ERT2 Control by 2-way ANOVA with Šidák’s multiple-comparisons test. Scale bars: 100 μm.