Bing Zhou1, Caizhi Liu2, Lingyan Xu2, Youwen Yuan3, Jiejie Zhao1, Wenjun Zhao2, Yiyan Chen1, Jin Qiu2, Meiyao Meng2, Ying Zheng2, Dongmei Wang2, Xin Gao1, Xiaoying Li1, Qihong Zhao4, Xiaohui Wei4, Duojiao Wu1, Huijie Zhang3, Cheng Hu5, Xiaozhen Zhuo6, Minghua Zheng7,8, Hua Wang4, Yan Lu1, Xinran Ma2. 1. The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China. 2. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China. 3. Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China. 4. Department of Oncology, The First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, People's Republic of China. 5. Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China. 6. Department of Cardiology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, People's Republic of China. 7. NAFLD Research Centre, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. 8. Institute of Hepatology, Wenzhou Medical University, Wenzhou, People's Republic of China.
Abstract
BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive triglycerides (TGs) in hepatocytes. Obesity is a major risk factor for developing fatty liver, although the intracellular molecular basis remains largely unclear. N6 -methyladenosine (m6 A) RNA methylation is the most common internal modification in eukaryotic mRNA. APPROACH AND RESULTS: In the present study, by m6 A sequencing and RNA sequencing, we found that both m6 A enrichment and mRNA expression of lipogenic genes were significantly increased in leptin-receptor-deficient db/db mice. Importantly, our results showed that YT521-B homology domain-containing 2 (Ythdc2), an m6 A reader, was markedly down-regulated in livers of obese mice and NAFLD patients. Suppression of Ythdc2 in livers of lean mice led to TG accumulation, whereas ectopic overexpression of Ythdc2 in livers of obese mice improved liver steatosis and insulin resistance. Mechanistically, we found that Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c, fatty acid synthase, stearoyl-CoA desaturase 1, and acetyl-CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression. CONCLUSIONS: Our findings describe an important role of the m6 A reader, Ythdc2, for regulation of hepatic lipogenesis and TG homeostasis, which might provide a potential target for treating obesity-related NAFLD.
BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive triglycerides (TGs) in hepatocytes. Obesity is a major risk factor for developing fatty liver, although the intracellular molecular basis remains largely unclear. N6 -methyladenosine (m6 A) RNA methylation is the most common internal modification in eukaryotic mRNA. APPROACH AND RESULTS: In the present study, by m6 A sequencing and RNA sequencing, we found that both m6 A enrichment and mRNA expression of lipogenic genes were significantly increased in leptin-receptor-deficient db/db mice. Importantly, our results showed that YT521-B homology domain-containing 2 (Ythdc2), an m6 A reader, was markedly down-regulated in livers of obesemice and NAFLDpatients. Suppression of Ythdc2 in livers of lean mice led to TG accumulation, whereas ectopic overexpression of Ythdc2 in livers of obesemice improved liver steatosis and insulin resistance. Mechanistically, we found that Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c, fatty acid synthase, stearoyl-CoA desaturase 1, and acetyl-CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression. CONCLUSIONS: Our findings describe an important role of the m6 A reader, Ythdc2, for regulation of hepatic lipogenesis and TG homeostasis, which might provide a potential target for treating obesity-related NAFLD.