Inhibiting TET1 alleviates non‐alcoholic liver disease progression by targeting lipid metabolic pathways.

Abstract

Background & AimNon‐alcoholic fatty liver disease (NAFLD) affects more than one‐quarter of adults worldwide, with 60% in diabetic patients and 90% in obese people. Epigenetic modifications are highly associated with NAFLD development. It has been reported that the 5‐hydroxymethylcytosine (5hmC) epigenetic modification and its catalyzing enzymes, the Ten‐eleven translocation (TET) family dioxygenases, are involved in NAFLD progression. However, it remains unclear how the TET family enzymes participate in NAFLD development. The current study was aimed to clarify the involvement of TET family proteins in NAFLD.MethodsGenetic TET1 knockout mice were generated and challenged with a high fat diet (HFD) for 16 weeks. Liver and serum lipid contents were analyzed by biochemical assays. To determine liver injuries, histological staining and liver functional assays were used. Immunoblotting and RNA sequencing were adopted for the study of molecular mechanisms associated with TET‐mediated NAFLD.ResultsThe HFD challenge led to significant down‐regulation of TET1 and TET3 in male mice, but a greater extent in TET1. Thus, TET1 knockout (KO) male mice were generated to evaluate how TET1 KO impacts NAFLD development. TET1 KO decreased mouse body weight without affecting the ratio of liver weight over body weight and fat weight over body weight, suggesting that TET1 KO may not significantly impact the development of liver and adipose tissue. Unexpectedly, TET1 KO substantially suppressed HFD‐induced steatosis and liver injuries.Mechanism studies revealed that the TET1‐mediated fatty liver development is not related to food/water consumption and fed glucose levels. Although the crucial metabolic regulators, including Akt and AMPK/LKB1 signaling pathways, are highly disrupted by the HFD feeding, no differences between TET1 wild‐type and KO mice were found. Interestingly, serum cholesterol, hepatic triglyceride, and cholesterol were substantially decreased in TET1 KO mice. The RNA sequencing results illustrated significant down‐regulation of those genes involved in lipid, fatty acid, and cellular lipid metabolic processes in TET1 KO mice. With further bioinformatics analysis, it was found that substantial down‐regulation of PPARγ, CD36, and ABCG1 in TET1 KO mice may contribute to the alleviation of NAFLD progression. The functions of PPARγ, CD36, and ABCG1 are highly associated with fatty acid synthesis, uptake, and cholesterol synthesis and efflux, respectively, thus supporting the role of TET1 in NAFLD development through targeting lipid metabolic pathways.ConclusionWe demonstrated that TET1 down‐regulation plays a protective role in NAFLD progression by targeting lipid metabolism.