Novel Role of Hepatic SEL1L-HRD1 ERAD in FGF21 Gene Transcription

More than one third (36.5%) of US adults are obese, with an estimated annual medical cost of approximately $200 billion per year. Obesity is believed to account for 80-85% of the risk of developing type 2 diabetes (T2DM). Fibroblast growth factor (FGF21), a metabolic hormone produced by liver that plays important roles in lipid and glucose metabolism, has emerged as a new therapeutic target for the treatment of obesity and diabetes. However, how the production of FGF21 is tightly controlled remain as a mystery. By analyzing the phenotypes of mice with genetic deletion of either SEL1L (Qi lab) or HRD1 (Fang lab) genes specifically in liver, we discovered that both SEL1L and HRD1 plays critical roles in controlling FGF21 liver production. As SEL1L and HRD1 form a complex in the endoplasmic reticulum (ER)-associated degradation (ERAD), a process responsible for the recruitment and retrotranslocation of ER proteins for cytosolic proteasomal degradation. As a consequence, SEL1L-HRD1 ERAD-null mice resemble the phenotypes of FGF21 gain-of-function model. Based on these strong preliminary data, we will test the hypothesis that hepatic SEL1L or HRD1 functions as an ERAD complex and controls systemic energy metabolism at least in part mediated through the CREBH-FGF21 axis. As defined in the scope of the work and multiple PI plan, Fang lab will focus on the studies of novel molecular mechanisms underlying HRD1 in regulating liver FGF21 production. Together with the research in Qi laboratory, we will define for the first time, the liver-specific SEL1L-HRD1 ERAD physiological functions and reveal previously unappreciated critical molecular mechanisms in systemic metabolism regulation. In addition, our studies will provide a rational for modulation of hepatic ERAD in prevention and treatment of metabolic disorders such as obesity and T2DM.