Study On AhR-PPAR? Interaction And Its Effect On Adipose Differentiation

BackgroundAccording to the latest statistics from the WHO,the obesity rate has increased year by year since 1975.The incidence of various diseases associated with obesity,such as diabetes,atherosclerosis,cardiovascular disease or liver disease,is also on the rise.The pathogenesis of these obesity-related diseases is related to the peroxisome proliferator-activated receptor ?(PPAR?)signaling pathway.PPARy belongs to the ligand-activated transcription factor nuclear receptor superfamily and is highly expressed in adipose tissue.It is reported that PPAR? is an essential regulator of adipogenesis and is involved in controlling glucose homeostasis and insulin sensitivity.Meanwhile,PPARy is highly related to type II diabetes and hypertension,due to important roles in the occurrence and development of inflammation,atherosclerosis,insulin resistance and tumors.Therefore,studying the signaling pathways that regulate PPARy is critical for the prevention and treatment of obesity and its related diseases.In 2017,our laboratory found that the scaffold protein CUL4B is involved in the negative regulation of PPAR?.Cul4b deficient mice showed elevated levels of PPARy protein,increased levels of adipocyte differentiation,and sensitivity to insulin.This is due to the formation of the CUL4B-related ubiquitin ligase complex,which promotes polyubiquitination of the substrate PPARy and proteasome-dependent protein degradation.However,in this complex,the protein component that directly binds(recruits)the substrate PPARy remains unknown.This project first clarnfied that aryl hydrocarbon receptor(AhR)is the key protein involved in the recruitment of PPARy.As a ligand-inducible transcription factor widely distributed in multiple organs,AhR is involved in the regulation of various biological functions and is closely related to the occurrence of various tumors.AhR was initially found to be associated with toxic reactions.Recently,it has been found that the deletion or activation of the AhR gene leads to an imbalance of glucose and lipid metabolism in mice,but the molecular mechanism involved is still unknown.ObjectiveTo study the effect of AhR on adipogenic differentiation;To determine that AhR affects the level of adipose differentiation by affecting the stability of PPARl? protein;To investigate the interacting domains between AhR and PPARy.Results1.In the process of adipose differentiation(3T3-L1 cells),overexpression of AhR inhibits adipose differentiation,and knockdown of AhR promotes adipose differentiation;2.Overexpression or knockdown of AhR does not affect the transcription level of PPARl?,but it affects the protein level of PPAR?.For example,knockdown of AhR increases the protein level of PPAR?,while overexpression of AhR decreases the protein level of PPAR?.3.AhR directly binds(recruits)the substrate PPARy and co-immunoprecipitated with CUL4B.4.The 1-232 amino acid region of PPARy and the 188-403 amino acid region of AhR are the major regions involved in protein-protein interaction.ProspectsWe studied the recognition region of AhR-PPAR?,which can help us to enhance or stabilize the PPARy protein level by inhibiting the ubiquitination degradation pathway,thereby enhancing the function of PPARy.Our study provides an important theoretical basis for enhancing the body's sensitivity to insulin and thus treating type? diabetes.