Wednesday, April 2, 2025
4/2/2025
TET1 in non-alcoholic fatty liver disease development - Project summary: The long-term goal of this project is to determine the role of TET1 in non-alcoholic fatty liver disease (NAFLD) development and progression. Several recent studies have suggested that the DNA methylation of specific genes, such as insulin growth factor-like protein 2 (IGFBP2), is highly associated with NAFLD development. Besides, global DNA methylation is decreased in NAFLD patients. The extent of DNA methylation is negatively correlated with inflammation and fibrosis in these patients, suggesting the importance of DNA methylation in NAFLD progression. DNA methylation is catalyzed by the DNA methyltransferases (DNMTs), including DNMT1, DNMT3a, and DNMT3b. In contrast, active DNA demethylation is a series of biochemical reactions catalyzed by the ten-eleven translocation (TET) methylcytosine dioxygenase family proteins, including TET1, TET2, and TET3. It was reported that DNMT1 deficiency inhibited steatosis in an alcohol-induced steatosis mouse model, thus contradicting the clinical findings. Similarly, liver-specific TET2 and TET3 knockout (KO) mice with elevated global DNA methylation in the liver developed fatty liver diseases spontaneously, again contradicting the clinical results. Interestingly, it has been shown that the whole body and adipocyte-specific TET1 KO mice are both protected from obesity in the high-fat diet (HFD) feeding model, linking the protective role of TET1 in NAFLD. Our unpublished data further demonstrated that two different whole-body TET1 KO mouse models have improved liver functions and lipid profiles when challenged with an HFD feeding. We performed RNA-Seq using the liver samples and found that TET1 promotes NAFLD possibly through targeting CD36 and IGFBP2 which are both involved in hepatic lipid metabolisms. Therefore, based on the previous findings and our unpublished data, we hypothesize that expression of TET1 leads to altered epigenetic gene regulations in the liver, contributing to the NAFLD development. We propose three specific aims to evaluate our hypothesis. 1) We will determine the role of hepatic TET1 in NAFLD progression. Liver specific TET1 KO mice will be used to determine if depleting hepatic TET1 protects NAFLD progression. Primary isolated control and TET1 KO hepatocytes from mice will be used to determine lipid metabolic changes. Besides, control and TET1 KO human hepatocytes established using the CRISPR/Cas9 system will be used to determine if the findings in mice can be translated into human pathobiology. 2) We will determine the mechanisms by which TET1 is involved in NAFLD development by investigating if TET1’s enzymatic activity is required for the target gene regulation. Besides, the impacts of reversing TET1 signaling cascade on NAFLD progression will be determined in vitro and in vivo. 3) We will characterize the impacts of TET1 on non-parenchymal cells during NAFLD progression, including non-alcoholic steatohepatitis associated macrophages which are highly correlated with NAFLD disease severity. Accomplishment of the proposal will yield results toward establishing TET1 as a potential target in NAFLD.
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