Feifei Zhang1, Zhimin Hu1, Gaopeng Li2, Shaofeng Huo1, Fengguang Ma1, Aoyuan Cui1, Yaqian Xue1, Yamei Han1, Qi Gong1, Jing Gao1, Hua Bian3,4, Zhuoxian Meng5, Haifu Wu6, Gang Long7, Yi Tan8, Yan Zhang2, Xu Lin1, Xin Gao3,4, Aimin Xu9,10,11, Yu Li1. 1. CAS Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. 2. College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong, China. 3. Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China. 4. Fudan Institute for Metabolic Diseases, Shanghai, China. 5. Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. 6. Metabolic and Bariatric Surgery of Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. 7. Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China. 8. Pediatric Research Institute at the Department of Pediatrics, Wendy L. Novak Diabetes Care Center, University of Louisville, Louisville, KY. 9. State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China. 10. Department of Medicine, The University of Hong Kong, Hong Kong, China. 11. Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
Abstract
Insulin is critical for the regulation of de novo fatty acid synthesis, which converts glucose to lipid in the liver. However, how insulin signals are transduced into the cell and then regulate lipogenesis remains to be fully understood. Here, we identified CREB/ATF bZIP transcription factor (CREBZF) of the activating transcription factor/cAMP response element-binding protein (ATF/CREB) gene family as a key regulator for lipogenesis through insulin-Akt signaling. Insulin-induced gene 2a (Insig-2a) decreases during refeeding, allowing sterol regulatory element binding protein 1c to be processed to promote lipogenesis; but the mechanism of reduction is unknown. We show that Insig-2a inhibition is mediated by insulin-induced CREBZF. CREBZF directly inhibits transcription of Insig-2a through association with activating transcription factor 4. Liver-specific knockout of CREBZF causes an induction of Insig-2a and Insig-1 and resulted in repressed lipogenic program in the liver of mice during refeeding or upon treatment with streptozotocin and insulin. Moreover, hepatic CREBZF deficiency attenuates hepatic steatosis in high-fat, high-sucrose diet-fed mice. Importantly, expression levels of CREBZF are increased in livers of diet-induced insulin resistance or genetically obese ob/ob mice and humans with hepatic steatosis, which may underscore the potential role of CREBZF in the development of sustained lipogenesis in the liver under selective insulin resistance conditions. CONCLUSION: These findings uncover an unexpected mechanism that couples changes in extracellular hormonal signals to hepatic lipid homeostasis; disrupting CREBZF function may have the therapeutic potential for treating fatty liver disease and insulin resistance. (Hepatology 2018).
Insulin is critical for the regulation of de novo fatty acid synthesis, which converts glucose to lipid in the liver. However, how insulin signals are transduced into the cell and then regulate lipogenesis remains to be fully understood. Here, we identified CREB/ATF bZIP transcription factor (CREBZF) of the activating transcription factor/cAMP response element-binding protein (ATF/CREB) gene family as a key regulator for lipogenesis through insulin-Akt signaling. Insulin-induced gene 2a (Insig-2a) decreases during refeeding, allowing sterol regulatory element binding protein 1c to be processed to promote lipogenesis; but the mechanism of reduction is unknown. We show that Insig-2a inhibition is mediated by insulin-induced CREBZF. CREBZF directly inhibits transcription of Insig-2a through association with activating transcription factor 4. Liver-specific knockout of CREBZF causes an induction of Insig-2a and Insig-1 and resulted in repressed lipogenic program in the liver of mice during refeeding or upon treatment with streptozotocin and insulin. Moreover, hepatic CREBZF deficiency attenuates hepatic steatosis in high-fat, high-sucrose diet-fed mice. Importantly, expression levels of CREBZF are increased in livers of diet-induced insulin resistance or genetically obese ob/ob mice and humans with hepatic steatosis, which may underscore the potential role of CREBZF in the development of sustained lipogenesis in the liver under selective insulin resistance conditions. CONCLUSION: These findings uncover an unexpected mechanism that couples changes in extracellular hormonal signals to hepatic lipid homeostasis; disrupting CREBZF function may have the therapeutic potential for treating fatty liver disease and insulin resistance. (Hepatology 2018).