Insulin is critical for the regulation of glucose homeostasis whose dysfunction leads to excessive triglyceride accumulation in the liver, the hallmark of nonalcoholic fatty liver disease (NAFLD) pathology. However, the mechanisms of insulin signals are transduced into the cell, and then regulate lipogenesis remains to be fully understood.
Base on the recent findings that AMP-activated protein kinase (AMPK)-mediated phosphorylation of sterol regulatory element binding protein (SREBP) in the regulation of hepatic lipogenesis (Li, Y, et al, Cell Metabolism, 2011), a team of scientists led by Professor LI Yu from Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences demonstrates that a novel activating transcription factor/cAMP responsive element binding (ATF/CREB) family transcription cofactor, called CREB/ATF bZIP transcription factor (CREBZF), senses insulin signaling and stimulates expression of lipogenic genes. They demonstrate that CREBZF-dependent inhibition of insulin induced gene (Insig) represent a molecular mechanism by which extracellular hormonal cues are transduced into the cell, and then regulate Insig-mediated feedback regulation of lipogenesis, which may contribute to hepatic steatosis, dyslipidemia and insulin resistance.
In this study, scientists characterize CREBZF as a key lipogenic activator for hepatic fatty acid synthesis. In vivo and in vitro studies illustrated that CREBZF activity is elevated in obesity and nutrient overload, which promotes lipogenesis and hepatic steatosis via Insig. During refeeding, insulin-induced activation of CREBZF inhibits Insig-2a expression in hepatocytes, allowing SREBP-1 to be processed and activation of fatty acid synthesis. The CREBZF/ATF4 heterodimer serves as the direct regulator transducing excessive nutrient and hormonal signaling to the transcriptional regulation of Insig-2a via the putative CCAAT enhancer binding protein-activating transcription factor (C/EBP-ATF) composite sequence. Hyperactivation of CREBZF may underscore the potential role of CREBZF in the development of sustained lipogenesis in the liver under selective insulin resistance conditions.
These findings conceptually advance our understanding of the hormonal regulation of hepatic lipogenesis via the novel ATF/CREB family transcription factor. Moreover, these findings may have therapeutic implications for hepatic steatosis, hyperlipidemia and insulin resistance.
This work was published online in Hepatology on April 10, 2018, doi: 10.1002/hep.29926 as a research article entitled “Hepatic CREBZF Couples Insulin to Lipogenesis by Inhibiting Insig activity and Contributes to Hepatic Steatosis in Mice”.
This study was funded by the grants from Ministry of Science and Technology of China (MOST), National Natural Science Foundation of China (NSFC) and Chinese Academy of Sciences (CAS).
Figure: The proposed model for the transcriptional regulation of Insig by CREBZF in the liver: potential therapeutic implication in hepatic lipid deregulation and hepatic steatosis (Image by Dr. LI Yu’s lab).
LI Yu, PhD
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
320 Yue Yang Road
Life Science Research Building A1816
Shanghai 200031, China
Phone: +86 (21) 54920753
Fax: +86 (21) 54920924