The Important Role Of HNF1b In Metabolic Disorders Model And Liver Regeneration Model

[Background] Hepatocyte nuclear factor 1b(Hepatocyte nuclear factor 1b,HNF1b)is essential for the development of liver and pancreas,mutations in different sites will lead to diabetes and liver disease,which is a new research hotspot in the field of life sciences in recent years.Reactive oxygen species(ROS)plays an important role in the pathogenesis of Type 2 diabetes(T2DM)and its complications.As a signal molecule,ROS is closely related to the embryonic development of the liver.The Previous studies have shown that the role of HNF1b in the development of liver-related diseases may be achieved by regulating in vivo ROS levels,but the specific mechanism is unclear.[Objective] In this study,metabolic disorders and liver regeneration models were designed by using polychlorinated biphenyls(PCBs)to observe that the key role of HNF1b in metabolic disorders and liver-related diseases,elucidate the interrelationships and interactions between HNF1b and oxidative stress,and to explore the concrete mechanism of the downstream signal network in the development and progression of related diseases.[Methods] 1.Mice were randomly divided into four groups: control group(Con),high fat diet group(HFD),high fat diet + PCB-153 group(HFD + PCB-153)and PCB-153 group(PCB-153).The mice of Con group were fed with normal diet.Mice in HFD group and HFD + PCB-153 group were fed with 45% high fat diet.Mice in HFD + PCB-153 and PCB-153 groups consumed water containing 4 mg / L PCB-153.Blood glucose,blood lipids and other indicators were detected after 3 months to test whether the metabolic disorder model was established successfully.2.Plasmid transfection,broad-spectrum antioxidant(N-acetyl-L-cysteine,NAC)and the inhibitor of nuclear transcription factor kappa B(NF-κB)pyrrolidine dithiocarbamate(PDTC)intervention were used to elucidate the specific mechanism of HNF1b,ROS and NF-κB in the metabolic disorder models.3.Partial-hepatectomized model was constructed.Western Blot and Dihydroethidium(DHE)staining were used to investigate the mechanism of HNF1b / ROS / NF-κB signaling pathway in liver regeneration process.[Results] 1.Blood sugar was elevated and insulin resistance was induced,when mice were fed with PCB-153 or HDF.Glucose metabolism abnormalities was aggravated in HFD + PCB-153 group,suggested that PCB-153 induced and aggravated glucose metabolism disorders caused by the high-fat diet.2.The level of triglycerides was elevated;volume of lipid droplets and weight of fat was increased,when mice were fed with PCB-153 or HDF.Lipid accumulation was aggravated in HFD + PCB-153 group,suggested that PCB-153 induced and aggravated lipid metabolism disorders caused by the high-fat diet.3.PCB-153 increased the expression of P65,interleukin-1ɑ,IL-1ɑ,interleukin-1(IL-6)m RNA in tissues and cells,PDTC inhibited elevation of IL-1ɑ and blood lipid,and insulin resistance induced by PCB-153,suggested that NF-κB-mediated inflammatory response was involved in glucose and lipid metabolism disorders induced by PCB-153.4.PCB-153 increased the level of ROS,decreased m RNA expression levels of HNF1b and antioxidant enzyme GPX1.The levels of ROS,P65 m RNA,triglycerides were elevated and insulin resistance was induced,when mice were peritoneal injection with exogenous NAC.The effect of HNF1b overexpression was similar with NAC administration,suggested that PCB-153-mediated Inflammation,lipid accumulation,and insulin resistance were associated with out of control in ROS regulation which is caused by HNF1b expression abnormal.5.In 70% partial-hepatectomized model,HNF1b,ROS and NF-κB increased firstly and then decreased with time after surgery.These trends were similar to the expression of proliferating cell nuclear antigen(PCNA)Protein expression,suggested that HNF1b / ROS / NF-κB signaling pathway may play an important role in liver regeneration.6.HNF1b Overexpression or NAC treatment,the levels of ROS,the expression of NF-κB、IL-6 and PCNA protein were decreased on the first day after surgery of 70% partial-hepatectomized,suggested that as signal molecules,low ROS levels affect liver regeneration and was not beneficial to liver repair.[Conclusions] 1.PCB-153 can induce or aggravate glucose and lipid metabolism disorders,possibly by increasing the level of ROS,primarily by down-regulating HNF1b expression,then enhancing the NF-κB-mediated inflammatory response,leading to lipid accumulation and glucose metabolism abnormality.2.HNF1b / ROS / NF-κB signaling pathway may play an important role in liver regeneration.Overexpression HNF1b or down regulation the levels of ROS,the expression of NF-κB was not beneficial to liver repair.