Non-alcoholic fatty liver disease (NAFLD) is now the most prevalent chronic liver disease in the world, with about 25% of patients progressing to non-alcoholic steatohepatitis (NASH). NASH is a severe type of non-alcoholic fatty liver disease, in patients with hepatic inflammatory lesions or fibrotic lesions in addition to lipid deposition in the liver. NASH is a potentially fatal disease leading to liver cirrhosis, liver failure, and hepatocellular carcinoma. However, the specific pathogenesis of NASH is still unclear, and there is no clinical effective therapeutic agent.
Li Yu from Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences published a research paper entitled: Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression in Hepatology journal.
In this study, the mechanism of CREB / ATF basic leucine zipper transcription factor CREBZF in the regulation of non-alcoholic steatohepatitis (NASH), which provided a new idea and strategy for exploring the regulation mechanism of "hepatocyte-stellate cell" dialogue and the treatment of clinical non-alcoholic steatohepatitis.
Recently, researcher Li's team found that CREBZF plays an important role in regulating insulin-induced liver lipid anabolism and liver injury or liver tissue regeneration induced by liver resection (Zhang F, et al, Hepatology 2018; HuZ, et al, Hepatology 2020, CuiA, et al, Diabetes 2021), but the effect of CREBZF on NASH is unknown. In order to explore the potential role of CREBZF in NASH, the research team using CREBZF hepatocyte-specific knockout mice, by constructing high fat high fructose high cholesterol feed NASH mouse model, found that CREBZF hepatocyte-specific knockdown can significantly alleviate liver inflammatory reaction and fibrosis lesions, confirmed that CREBZF plays an important role in regulating the development of NASH.
Through liver transcriptome sequencing (scRNA-seq, Bulk RNA-seq), combined with cell co-culture experiments, the research team found that CREBZF accelerated the activation of hepatic stellate cells by promoting the expression and secretion of the extracellular matrix protein OPN (osteopontin, osteopontin) in hepatocyte cells. Liver complement of OPN in CREBZF hepatocyte-specific knockout mice can accelerate hepatic stellate cell activation and hepatic fibrosis lesions.
In addition, the research team used MicroRNA sequencing to show that CREBZF targeted and increased OPN mRNA expression by inhibiting miR-6964-3p transcription in hepatocytes. In clinical NASH liver samples, both CREBZF and OPN were induced activation in hepatocytes, suggesting that this regulatory mechanism is of potential clinical significance for NASH diagnosis and treatment.
Map of liver CREBZF as a regulator of liver fibrosis checkpoint and NASH progression: During NASH progression, excessive activation of hepatocyte CREBZF increases the expression and secretion of pro-fibrogenic factor OPN by inhibiting miR-6964-3p, thus accelerating hepatic stellate cell activation and liver fibrosis. Targeting CREBZF may be an ideal strategy to treat the two key pathological stages of lipid deposition and collagen deposition during the pathogenesis of NAFLD and NASH.
This study revealed the molecular mechanism that the transcription factor CREBZF increases OPN protein expression and secretion by negatively regulating miR-6964-3p, and then aggravates liver fibrosis and NASH. CREBZF May be a key checkpoint in regulating HSC activation associated with liver fibrosis, and CREBZF-OPN pathway activation may be an important trigger to aggravate the progression of NASH pathology. Meanwhile, this study suggests that inhibition of hepatic CREBZF may be a novel strategy to reverse liver fibrosis with the pathogenesis of NASH.
Prof. Li Yu, Prof. Cui Aoyuan, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, and Professor Xu Yong of Southwest Medical University are the corresponding authors of the paper; Dr. Ma Feng Feng, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, is the first author of the paper. The research was supported by the Key Research and Development Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, the China Postdoctoral Science Foundation, and the Luzhou Municipal Science and Technology Strategic Cooperation Project Fund of Southwest Medical University, as well as the Public Technology Center of Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences.
