Xiaodong Chen’s research while affiliated with Huazhong Agricultural University and other places

As a metabolic disease, fatty liver hemorrhagic syndrome (FLHS) has emerged as a major cause of noninfectious mortality in laying hens, resulting in substantial economic losses to the poultry industry. This study aimed to investigate the therapeutic effects of magnolol on FLHS in postpeak laying hen model, focusing on lipid metabolism, antioxidative capacity, and potential molecular mechanisms of action. We selected 150 Xinhua laying hens aged 50 wk and divided them into normal diet group (ND), high-fat diet group (HFD), 100 mg/kg magnolol group (MG100), 300 mg/kg magnolol group (MG300), 500 mg/kg magnolol group (MG500) on average. The experiment lasted for 6 wk, and liver samples were collected from the hens at the end of the experiment. The results demonstrated that the inclusion of magnolol in the diet had a significant impact on various factors. It led to a reduction in weight, an increase in egg production rate, a decrease in blood lipid levels, and an improvement in abnormal liver function, liver steatosis, and oxidative stress. These effects were particularly prominent in the MG500 group. The RNA—Seq analysis demonstrated that in the MG500 group, there was a down-regulation of genes associated with fatty acid synthesis (Acc, Fasn, Scd, Srebf1, Elovl6) compared to the HFD group. Moreover, genes related to fatty acid oxidation (CPT1A and PGC1α) were found to be up-regulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of these differentially expressed genes indicated their enrichment in the PPAR signaling pathway. These findings demonstrate that magnolol can mitigate FLHS by inhibiting fatty acid synthesis and promoting fatty acid oxidation. This discovery offers a novel approach for treating FLHS in laying hens, reducing the economic losses associate with FLHS.

Muscular dysplasia is a common muscle disease, but its pathological mechanism is still unclear. Adipose is originally identified as a highly conservative and widely expressed anti-obesity gene, and our previous study has reported that Adipose is also a positive regulator of myogenesis. Considering the vital role of during muscle development, this study was to demonstrate a potential relationship between Sirtuin1 and Adipose and clarified the mechanism by which Adipose regulated muscle development. Our results showed that the muscle fiber cross-sectional area and myosin heavy chain protein level were significantly reduced in Sirtuin1+/- mice. Moreover, the longitudinal section of muscle fibers was obviously irregular. Sirtuin1 knockdown significantly reduced the expression levels of Adipose and its upstream transcriptional regulator Kruppel like factor 15 and notably inhibited the AMP-activated protein kinase α-peroxisome proliferator-activated receptor gamma coactivator 1α signaling pathway in skeletal muscle. However, Adipose over-expression activated this signaling pathway and promoted mitochondrial biosynthesis in C2C12 myoblasts. Adipose over-expression also enhanced glucose absorption of C2C12 cells, suggesting the increased needs for cells for metabolic substrates. In C2C12 cells with hydrogen peroxide treatment, Adipose over-expression repressed hydrogen peroxide-elicited apoptosis and mitochondrial loss, while Sirtuin1-specific inhibitor dramatically weakened these roles of Adipose. Taken together, our findings reveal that Adipose rescues the adverse effects of Sirtuin1 deficiency or hydrogen peroxide on muscle development by activating the AMP-activated protein kinase α- peroxisome proliferator-activated receptor gamma coactivator 1α pathway to promote mitochondria synthesis, which provides theoretical basis for developing new therapeutic targets against some muscle diseases.

Nonalcoholic fatty liver disease (NAFLD) occurs when excess fat is stored in the liver and it is strongly linked with metabolic syndrome and oxidative stress. Selenium (Se) is an essential micronutrient in animals, which has a variety of biological functions, including antioxidant and anti-inflammatory. However, the exact effect of dietary selenium on NAFLD and the underlying molecular mechanism are not yet clear. Herein, we fed a high-fat diet (HFD) to C57BL/6 mice to construct an in vivo NAFLD model, treated AML-12 cells with palmitic acid (PA) to construct an in vitro NAFLD model, and AML-12 cells were stimulated with H2O2 to induce hepatocyte oxidative stress and then treated with adequate selenium. We observed that adequate selenium significantly improved the hepatic injury and insulin resistance in HFD mice, and decreased the fat accumulation and the expression of lipogenic genes in PA-induced AML-12 cells. Meanwhile, selenium significantly inhibited the production of reactive oxygen species (ROS), inhibited apoptosis, and restored mitochondrial number and membrane potential in PA- induced AML-12 cells. In addition, selenium can promote selenoproteinP1 (SEPP1) synthesis to regulate the Kelch-like ECH-associated protein 1 (KEAP1)/NF-E2-related factor 2 (NRF2) pathway, so as to defend against hepatocyte oxidative stress. These findings suggest that dietary selenium supplementation can effectively resist hepatic injury and insulin resistance during NAFLD development, and regulate the KEAP1/NRF2 pathway to resist oxidative stress by promoting SEPP1 synthesis.

Aim Nonalcoholic fatty liver disease (NAFLD) has become a global epidemic, but its pathogenesis is unclear. STEAP4, a member of six transmembrane protein family, integrates inflammatory and metabolic responses. Our present aim is to explore the roles of STEAP4 in maintaining cellular homeostasis and improving high-fat-diet (HFD)-caused oxidative stress in hepatocytes. Main methods NAFLD model was established by HFD-feeding mice. The effects of over-nutrition on liver were detected by serum biochemical analysis and bulk RNA-seq. The levels of gene expression were measured by QPCR and Western Blot. Immunofluorescent staining was applied to determine the localization of STEAP4. AMPK agonist was employed to investigate the link between STEAP4 and AMPK pathway. Key findings Sus scrofa STEAP4 (sSTEAP4) relieved oxidative stress and rescued the viability of hepatocytes. sSTEAP4 increased AKT phosphorylation and SOD2 level in hepatocytes, whether or not treated with H2O2, suggesting sSTEAP4 has regulatory effects on insulin signaling and antioxidant pathways. However, sSTEAP4 inhibited AMPK phosphorylation and Beclin1/LC3 expression under H2O2-deficiency situation, but the results were conversed with H2O2 stimulation. The cellular ER stress was aggravated with the increased energy during oxidative stress, indicating that sSTEAP4 might regulate the energetic communication between ER and mitochondria by intervening mitochondrial energy production. In addition, sSTEAP4 was demonstrated to localize in the membranes of plasma and ER in HepG2 hepatocytes. Significance Our results reveal that sSTEAP4 based on the needs of cell itself to improve hepatic oxidative stress and HFD-caused NAFLD, which might provide a new therapeutic scheme for NAFLD.

Non-alcoholic fatty liver disease (NAFLD) has developed into the world's largest chronic epidemic. In NAFLD, hepatic steatosis causes hepatocytes dysfunction and even apoptosis. The liver has a strong restoration or regeneration ability after an injury, however, it is unclear through which pattern fatty liver injury in NAFLD is repaired and what the repair mechanism is. Here, we found that in the high-fat diet (HFD)-induced NAFLD mice model, fatty liver injury caused the significant ductular reaction (DR), which is a marker to promote the repair of liver injury. SOX9⁺ and HNF4α⁺ biphenotype also suggested that hepatic progenitor cells (HPCs) were activated by fatty liver injury in the HFD-elicited NAFLD mice model. Concurrently, fatty liver injury also activated the Wnt/β-catenin signal pathway, which is a necessary process for HPC differentiation into mature hepatocytes. However, Sirt1 knockdown weakened HPC activation and Wnt/β-catenin signal in Sirt1+/− mice with HFD feeding. In rat-derived WB-F344 hepatic stem cell line, Sirt1 overexpression (OE) or Sirt1 activator–Resveratrol promoted HPC differentiation via activating Wnt/β-catenin signal pathway. Glycogen PAS staining demonstrated that Sirt1 OE promoted WB-F344 cells to differentiate into mature hepatocytes with glycogen synthesis ability, while Sirt1 inhibitor EX527 or Wnt/β-catenin pathway inhibitor HF535 decreased glycogen positive cells. Together, our data suggested that Sirt1 plays a vital role in activating HPCs to repair fatty liver injury or promote liver regeneration through the Wnt/β-catenin signal pathway in NAFLD, which might provide a new strategy for fatty liver injury or NAFLD therapy.

Aims Chemerin is abundant in patients with high body mass index and metabolic syndrome possibly due to its activation in adipogenesis and glucose intolerance. It has reported that sera chemerin is positively associated with fatty liver with little known underlying mechanisms. Our aim is to study the role of chemerin in hepatic lipid metabolism. Main methods Oil Red O staining and TG quantitative assay were used to detect intracellular lipid accumulation. PCR, QPCR and western blot were applied to measure lipid metabolism-related genes, CMKLR1, GPR1 and inflammation marker genes. Luciferase reporter assay was employed to uncover the down-regulation of proximate promoter activities of CMKLR1 and GPR1 by SREBP1c. Antibody neutralization assay was used to address the effects of chemerin on hepatic lipid synthesis. Key findings Over-expression of chemerin led to passive lipid accumulation, in human hepatoma cell line HepG2. The disable form of chemerin (chemerin 21–158) and active chemerin (chemerin 21–157) performed strongly effects on lipid metabolism in HepG2 cells. Heterologous expression of CMKLR1 or G-protein coupled receptor1 (GPR1) played similar roles in hepatocyte lipid metabolism as chemerin. Chemerin exerted its effects on lipid metabolism via GPR1 in HepG2 cells. Furthermore, free fatty acids and high concentration insulin inhibited chemerin expression. Consistently, the key lipogenic transcription factor Sterol regulatory element binding protein 1c suppressed chemerin mRNA expression and proximate promoter activities of CMKLR1 and GPR1. Significance It implied the existence of negative feed-back regulation and further confirmed the involvement of chemerin in hepatic lipid metabolism.