Study on the mechanism of Yishen tongluo formula improving abnormal lipid metabolism based on SREBPs pathway / 中国药房

OBJECTIVE To explore the mechanism of Yishen tongluo formula （YSTLF） in improving abnormal lipid metabolism based on the sterol regulatory element binding proteins （SREBPs） pathway. METHODS Using C57BLKS/J （db/db） mice as model and C57BLKS/J （db/m） mice as normal control， the mechanism of 1， 2.5 and 5 g/kg YSTLF improving abnormal lipid metabolism of db/db mice was investigated by determining the liver coefficient， the contents of serum total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein （LDL） and high-density lipoprotein （HDL）， observing steatosis and lipid accumulation in liver tissue of mice， detecting the protein expressions of SREBP-1 and SREBP-2 as well as mRNA transcription levels of Srebp- 1c， Srebp-2 and their downstream lipid metabolism-related target genes （Fasn， Acc1， Scd5， Fads1， Hmgcr， Dhcr24， Insig-1， Fdps） in liver tissue of mice. Using low-fat cultured human liver cancer cell HepG2 as an in vitro cell model for abnormal lipid metabolism， and 25-HC （SREBPs inhibitor， 10 μmol/L） as the control， the effects of 125， 250 and 500 μg/mL YSTLF on protein expressions of SREBP-1 and SREBP-2 as well as mRNA transcription of SREBP-1c， SREBP-2 and their downstream lipid metabolism-related target genes were investigated to verify the mechanism in vitro. RESULTS 1， 2.5， 5 g/kg YSTLF significantly reduced the levels of TC， TG and LDL， the percentage of lipid droplet-positive region in liver tissue and liver coefficient， significantly down-regulated protein expressions of Pre-SREBP-1， n-SREBP-1， Pre-SREBP-2 and n-SREBP-2， and mRNA transcription of Srebp-1c， Srebp-2 and their downstream target genes in liver tissue， while significantly increased HDL level， with statistical significance （P＜0.05 or P＜0.01）. In the cell experiment in vitro， the expressions of the above-mentioned proteins and genes in the cells treated with YSTLF at 125， 250 and 500 μg/mL for 24 hours were consistent with those in the animal experiment； there was no significant difference in the expressions of the above-mentioned proteins and genes between inhibitor control group and 250， 500 μg/mL YSTLF groups （P＞0.05）. CONCLUSIONS YSTLF can regulate the expression of transcription factor SREBPs， so as to inhibit the high expression of fatty acid and cholesterol synthesis-related genes， promote the degradation of TC and TG， improve the abnormality of lipid metabolism and inhibit lipid accumulation， thus playing the role of lipid-lowering.

Metformin regulates AMPK/SREBP-1 pathway and its clinical application / 中国临床药理学与治疗学

Metformin is one of the commonly used hypoglycemic drugs in clinical practice. In addition to hypoglycemia, there are a variety of medical biological values that have been constantly discovered and attracted much attention. In recent years, studies have shown that metformin through activation of AMPK inhibition of sterols regulating element binding protein 1 (SREBP-1) reduce lipid synthesis, in the treatment of liver steatosis, improve insulin sensitivity, prevention Metformin is one of the commonly used hypoglycemic drugs in clinical practice. In addition to hypoglycemia, there are a variety of medical biological values that have been constantly discovered and attracted much attention. In recent years, studies have shown that metformin through activation of AMPK inhibition of sterols regulating element binding protein 1 (SREBP-1) reduce lipid synthesis, in the treatment of liver steatosis, improve insulin sensitivity, prevention of atherosclerosis and cardiovascular dysfunction, tumor, polycystic ovary syndrome and adjuvant therapy of COVID-19 aspects play a role. Therefore, this article reviews the possible mechanism and clinical application of metformin in regulating glucose and lipid metabolism by inhibiting SREBP-1 through activating AMPK.

Effect of milk on sebaceous gland spots and the IGF-1/SREBP-1/ACC-1 signaling pathway in golden hamsters / 中华皮肤科杂志

Objective:To investigate the effect of milk on sebum secretion in golden hamsters, and to explore its possible mechanism of action.Methods:Eighteen golden hamsters were randomly and equally divided into 3 groups: blank control group receiving no intervention, whole-milk group gavaged with whole milk, and skimmed-milk group gavaged with skimmed milk. The gavage feeding was performed at a dose of 2.5 ml twice a day for 4 consecutive weeks. The maximum transverse diameter and maximum longitudinal diameter of bilateral sebaceous gland spots were measured on days 0, 7, 14, 21 and 28 after the start of intervention, and the area of sebaceous gland spots was calculated; at 24 hours after the last gavage, bilateral sebaceous gland spot tissues were resected, and subjected to immunohistochemical study to determine the expression of insulin-like growth factor-1 (IGF-1) /sterol regulatory element-binding protein-1 (SREBP-1) /acetyl-coenzyme A carboxylase (ACC-1) signaling pathway in sebaceous gland spots. Statistical analysis was carried out by using repeated measures analysis of variance, one-way analysis of variance for independent groups, Kruskal-Wallis H test, and least significant difference- t test for multiple comparisons. Results:Repeated measures analysis of variance showed that there was no significant difference in the area of sebaceous gland spots of golden hamsters among the 3 groups ( F= 0.96, P= 0.417) . The IGF-1 expression was significantly higher in the skimmed-milk group (0.39 ± 0.03) than in the blank control group (0.35 ± 0.03, t= 2.62, P= 0.021) and whole-milk group (0.33 ± 0.02, t= 3.82, P= 0.002) ; compared with the blank control group (0.36 ± 0.02) , the skimmed-milk group showed significantly increased SREBP-1 expression (0.42 ± 0.04, t= 2.64, P= 0.021) ; the ACC-1 expression was significantly higher in the skimmed-milk group (0.40 ± 0.03) and whole-milk group (0.40 ± 0.05) than in the blank control group (0.34 ± 0.03; t= 2.39, 2.47, P= 0.031, 0.026, respectively) . Conclusion:Milk may promote sebum secretion in golden hamsters through the IGF-1/SREBP-1/ACC-1 signaling pathway.

Research on the mechanism of hypoxia promoting the migration of lung adenocarcinoma A549 cells / 中国应用生理学杂志

Objective: To investigate the mechanism that hypoxia promotes the migration of lung adenocarcinoma A549 cells. Methods: A549 cells were cultured and cells that knockdown of acetyl-CoA carboxylase 1 (ACC1) were obtained by transfection with lentivirus, and cells that knockdown of sterol regulatory element-binding proteins-1 (SREBP-1) were obtained by treated with si-RNA. A549 cells were treated with hypoxia combined with hypoxia inducible factor-1α (HIF-1α) inhibitor PX-478 (25 μmol); Hypoxia combined with linoleic acid (LA) (20 μmol) treated A549 cells with ACC1 knockdown, and A549 cells with SREBP-1 knockdown were treated by hypoxia. Transwell migration assay was used to detect cell migration. Western blot was conducted to detect HIF-1α, ACC1 and epithelial mesenchymal transition (EMT) related proteins, Vimentin, E-Cadherin and SREBP-1; Real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) was performed to detect the changes of ACC1 and SREBP-1 mRNA in A549 cells after hypoxia and HIF-1α inhibitor PX-478 (25 μmol) treatment. Each experiment was repeated three times. Results: Compared with the normoxic control group, hypoxia promoted the migration of A549 cells (P＜0.01), and up-regulated the expressions of ACC1, HIF-1α (all P＜0.01) and SREBP-1 (P＜0.05). PX-478 (25 μmol) inhibited the migration of A549 cells induced by hypoxia and down-regulated the expression of SREBP-1 (all P＜0.05). ACC1 mRNA and SREBP-1 mRNA levels were increased after hypoxia treatment of A549 cells (all P＜0.05). The levels of ACC1 mRNA and SREBP-1 mRNA were decreased after A549 cells treated with hypoxia combined with PX-478 (25 μmol) for 24 h (P＜0.05, P＜0.01). Knockdown of SREBP-1 in A549 cells was obtained by transfection with si-RNA. Transwell migration assay showed the number of cell migration in si-SREBP-1 group was less than that in normoxia control group (P＜0.01). The si-SREBP-1 group and the si-NC group were treated with hypoxia. Compared with the control group, the number of cell migration in the si-SREBP-1 group was decreased (P＜0.01), however, the difference was not statistically significant compared with the normoxia si-SREBP-1 group (P＞0.05). Western blot showed that the expression of ACC1 in the si-SREBP-1 group was lower than that in the control group (P＜0.01). Compared with the control group, the expression of ACC1 was decreased after si-SREBP-1 group treated with hypoxia (P＜0.01). Knockdown of ACC1 inhibited the migration of A549 cells (P＜0.05). After knockdown of ACC1, the migration number of A549 cells under normoxia and 5% O2 conditions had no significant difference (P＞0.05). Application of LA under hypoxia condition rescued ACC1-knockdown induced inhibitory effect on hypoxia-promoted A549 cell migration (P＜0.05). Conclusion: Hypoxia promotes migration of lung adenocarcinoma A549 cells by regulating fatty acid metabolism through HIF-1α/SREBP-1/ACC1 pathway.

Influence of Schisandrae Fructus and compatible with Glycyrrhiza on level of serum lipids and synthesis pathway of triglyceride / 中国药理学通报

Aim To investigate the influence of Schisandrae Fructus ( Wuweizi in Chinese) and com¬patible with Glycyrrhiza ( Gancao in Chinese ) on the levels of serum lipids and their influence on liver syn¬thesis pathway of triglyceride ( TG ). Methods ICR mice were divided, according to weight randomized block method, into four groups; normal control group ( Control, C ), Schisandrae Fructus ethanolic extract group (SF) , Schisandrae Fructus compatible with Gly¬cyrrhiza ethanolic extract (SG) 1 : 1 and 1 : 1.5. The control group was intragastrically given normal saline (10 mL • kg-1), SF group, SG 1 : 1 and 1 : 1. 5 group were given the extract 3. 9 g • kg"1 in crude of Schisandrae Fructus for 10 days. The levels of TG, to¬tal cholesterol (TC) , low-density lipoprotein-cholester¬ol ( LDL-C ) and high-density lipoprotein-cholesterol ( HDL-C ) were detected by biochemical method, as well as alanine aminotransferase (ALT) activity. The activities of liver fatty acid synthase (FAS) and acctyl-COA carboxylase ( ACC ), and levels of GPAT, acy- CoA oxidase ( ACO ) were detected by enzyme immu¬noassay ( ELISA ). The protein expressions of sterol regulatory element-binding protein-lc (SREBP-lc) and peroxisome proliferator-activiated receptor-a ( PPARa ) were detected by immunohistochemistry technique. Results Compared with C group, the lev¬els of TG and TC increased significantly, the level of serum LDL-C decreased significantly, the activities of liver ACC and GPAT level increased markedly, the protein expression of SREBP-1 c was markedly up-regu¬lated, and the protein expression of PPARa was evi¬dently down-regulated in SF group. When compared with SF group, the levels of serum TG and ACO, the activities of serum ALT and GPAT apparently de¬creased in SG 1 : 1 group. The protein expression of SREBP-1 c in SG 1 : 1 and 1 : 1.5 group was signifi¬cantly down-regulated, and the protein expression of PPARa was markedly up-regulated. Conclusions High dose of SF can increase the serum TG and TC levels , and the mechanisms may be related to that SF can promote the expression of liver SREBP-lc, in¬crease the activities and levels of FAS, ACC and GPAT in TG synthesis pathway, and down-regulate protein expression of PPARct and ACO for promoting liver TG synthesis. Compatible with Glycyrrhiza can significantly improve the elevated blood lipids and the proteins in the TG synthesis pathway.

Relationship between serum SREBP-1, SAP and endocrine metabolism in patients with polycystic ovary syndrome / 中华内分泌外科杂志

Objective:To investigate the relationship between serum sterol regulatory element binding protein-1 (SREBP-1) , serum amyloid P (SAP) and endocrine metabolism in patients with polycystic ovary syndrome.Methods:75 patients with polycystic ovary syndrome (study group) and 70 healthy women (control group) admitted to the First People’s Hospital of Yuhang District from Mar. 2018 to Feb. 2020 were enrolled. Various indexes were detected in both groups, including body mass index (BMI) , SREBP-1, SAP, triglyceride (TG) , total cholesterol (TC) , high-density lipoprotein (HDL-C) , and low-density lipoprotein (LDL-C) , fasting blood glucose (FBG) , fasting insulin (FINS) , and insulin resistance index (HOMA-IR) . The study group was further divided into two subgroups according to BMI, overweight group and normal group. SREBP-1 and SAP were compared between the two groups. Pearson correlation analysis was used to analyze the correlation between SREBP-1, SAP, blood lipid index, blood glucose index and BMI in patients with polycystic ovary syndrome.Results:The body weight and BMI index of study group were higher than those of control group [ (72.23±4.84) kg vs (58.23±3.25) kg, (25.02±2.75) kg/m 2 vs (22.11±1.34) kg/m 2, P<0.05]. The levels of serum SREBP-1 and SAP in the study group were significantly higher than those in the control group [ (334.78±32.06) pg/ml vs (206.34±25.71) pg/ml, (206.34±25.71) mg/U vs (39.16 ±0.58) mg/U, P<0.05]. The expression levels of TG, TC, LDL-C, FBG, FINS, and HOMA-IR in the study group were higher than those in the control group [ (2.32±0.71) vs (1.53±0.52) , (4.85±0.54) vs (3.41±0.66) , (3.06±0.75) vs (2.11±0.89) , (6.45±0.62) vs (5.59±0.76) , (16.14±1.03) vs (13.02±1.34) , (1.67±0.38) vs (1.18± 0.26) , P<0.05]; HDL-C expression level in the study group was lower than that in the control group [ (1.43±0.56) vs (1.71±0.42) , P<0.05]. The levels of SREBP-1 and SAP in overweight group were higher than those in normal group [ (339.19±27.63) pg/ml vs (281.67±20.18) pg/ml, (53.26±0.59) mg/U vs (42.48±0.67) mg/U, P<0.05]. Serum SREBP-1 and SAP in the study group were positively correlated with TG, TC, LDL-C, HOMA-IR, and BMI, and were negatively correlated with HDL-C ( P<0.05) . Conclusion:SREBP-1 and SAP levels are elevated in patients with polycystic ovary syndrome, which are significantly correlated with TG, TC, LDL-C, HOMA-IR, BMI, and HDL-C, and can cause endocrine disorder by affecting glucose and lipid metabolism.

Protective effect of Xiaochaihu Decoction on non-alcoholic steatohepatitis model mice / 中草药

Objective: The protective effect of Xiaochaihu Decoction on non-alcoholic steatohepatitis (NASH) model mice was studied by constructing a methionine-choline deficiency (MCD) diet-induced NASH model in mice. Methods: C57BL/6 mice, as the research objects, were randomly divided into normal control group, model group, Xiaochaihu Decoction (high, medium and low doses) group, Yishanfu group and Qianggan Capsule group. The NASH model was established by feeding MCD feeds, and model intervention was carried out at the same time by giving different drugs in groups; Changes in body weight, daily food intake, and daily water volume of the mice were recorded during the experiment. HE staining of liver tissue was performed at the end of the experiment to observe pathological changes. and the levels of biochemical indicator of alanine aminotransferase (ALT), Aspartate aminotransferase (AST), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in serum, and the changes of TC and TG levels in liver tissue were detected, RT-PCR was used to detect the expression levels of fatty acid synthase (FAS) and sterol regulatory element binding protein 1c (SREBP-1c) in liver tissues. Results: Data such as mouse weight, daily food intake, daily water intake, and organ coefficients indicated that MCD diet-induced model mice showed weight loss, decreased intake, and decreased liver wet weight. The weight, intake and liver coefficient of mice in Xiaochaihu Decoction group were significantly higher than those in the model group; The results of HE staining showed that Xiaochaihu Decoction could significantly reduce the degree of steatosis and inflammation of liver tissue, and improve the morphology and structure of liver cells; The results of serum biochemical indicators showed that Xiaochaihu Decoction significantly reduced the levels of TG, TC, AST, ALT, IL-6, TNF-α and increased the level of HDL-C in NASH model mice; RT-PCR results showed that the gene expression levels of FAS and SREBP-1c in the liver tissue of the model group mice were significantly increased, and the administration of Xiaochaihu Decoction could significantly reduce the gene expression levels of FAS and SREBP-1c. Conclusion: Xiaochaihu Decoction has obvious protective effect on NASH mouse model induced by MCD diet. It may play a lipid-lowering role by regulating the expression of inhibitors of fatty acid synthetase genes (FAS, SREBP-1c), reducing fat accumulation, and inhibiting the expression of inflammatory factors to improve liver tissue damage.

Promoter methylation of SREBP-2 in circulating leukocytes correlates with relevant risk factors in patients with coronary artery disease / 中华检验医学杂志

Objective@#To examine the correlation between the promoter methylation of Sterol regulatory-element binding protein-2 (SREBP-2) and miR-33a expression as well as serum markers in patients with coronary artery disease (CAD).@*Methods@#The case-control study. 100 participants who underwent coronary angiography from August 2017 to April 2018 in TaiheHospital, Hubei University of Medicine, were recruited in this study.The methylation level of two fragments, including 12 CpG sites in the promoter region of SREBP-2, have been detected by pyrosequencing in 50 patients with coronary artery disease (CAD) and 50 non-CAD controls. Serum miR-33a level and a panel of 15 CAD related biomarkers were examined by qPCR and routine biochemistry methods.@*Results@#Methylation level of one CpG site (F1-4 loci) in SREBP-2 promoter region were significant higher in CAD patients than in controls(4.56%±0.70% vs 3.54%±0.72%, t=-3.864, P<0.001); methylation level of F1-4 site was negatively correlates with the serum miR-33a levels and high-density lipoprotein cholesterol (HDL-C) levels(r=-0.318, P=0.001; r=-0.225, P=0.024, respectively). Furthermore, F1-4 hypermethylation was an independent risk factor of CAD, independent of age, gender, histories of hypertension, hyperlipidemia, and diabetes(OR=2.452, 95%CI=1.398-4.299, P=0.002).@*Conclusion@#These results suggest that DNA methylation and miRNA might cooperate to regulate the lipid metabolism in CAD.

Therapeutic effects of dimethyldiguanide combined with clomifene citrate in the treatment of polycystic ovary syndrome

SUMMARY OBJECTIVE In view of the high incidence of polycystic ovary syndrome (PCOS) and the unsatisfactory therapeutic effects of dimethyldiguanide or clomifene citrate alone, our study aimed to investigate the therapeutic effects of dimethyldiguanide combined with clomifene citrate in the treatment of PCOS. METHODS A total of 79 patients with POCS and 35 healthy females were included, and endometrial biopsies were obtained. The sterol regulatory element-binding protein-1 (SREBP1) expression in endometrial tissues was detected by qRT-PCR. POC patients were randomly divided into group A (n=40) and group B (n=39). Patients in group A were treated with dimethyldiguanide combined with clomifene citrate, while patients in group B were treated with clomifene citrate alone. The number of mature follicles and cervical mucus score, follicular development rate and single follicle ovulation rate, cycle pregnancy rate, early miscarriage rate, ovulation rate, endometrial thickness, positive rate of three lines sign, follicle stimulating hormone level and luteinizing hormone level were compared between the two groups. RESULTS The expression level of SREBP1 was higher in PCOS patients than that in the healthy control. SREBP1 expression was inhibited after treatment, while the inhibitory effects of combined treatment were stronger than those of clomifene citrate alone. Compared with clomifene citrate alone, the combined treatment improved cervical mucus score, follicle development rate, single follicle ovulation rate, endometrial thickness, positive rate of three lines sign, and follicle-stimulating hormone level. CONCLUSION The therapeutic effect of combined treatment is better than clomifene citrate alone in the treatment of PCOS.

RESUMO OBJETIVO Tendo em vista a alta incidência de síndrome dos ovários policísticos (SOP) e os efeitos terapêuticos insatisfatórios da dimetildiguanida ou do citrato de clomifeno isoladamente, nosso estudo teve como objetivo investigar os efeitos terapêuticos da dimetildiguanida associada ao citrato de clomifeno no tratamento da SOP. MÉTODOS Um total de 79 pacientes com POCS e 35 mulheres saudáveis foram incluídos, e biópsias endometriais foram obtidas. A expressão da proteína de ligação do elemento regulador de esterol-1 (SREBP1) nos tecidos endometriais foi detectada por qRT-PCR. Pacientes POC foram divididos aleatoriamente em grupo A (n=40) e grupo B (n=39). Os pacientes do grupo A foram tratados com dimetildiguanida combinada com citrato de clomifeno, enquanto os pacientes do grupo B foram tratados apenas com citrato de clomifeno. O número de folículos maduros e muco cervical, taxa de desenvolvimento folicular e taxa de ovulação, taxa de gravidez, abortamento precoce, taxa de ovulação, espessura endometrial, taxa positiva de três linhas, nível de hormônio folículo estimulante e nível de hormônio luteinizante foram comparados entre os dois grupos. RESULTADOS O nível de expressão do SREBP1 foi maior nos pacientes com SOP do que no controle normal. A expressão de SREBP1 foi inibida após o tratamento, enquanto os efeitos inibidores do tratamento combinado foram mais fortes do que os do citrato de clomifeno isoladamente. Comparado com o citrato de clomifeno sozinho, o tratamento combinado melhorou significativamente a pontuação do muco cervical, a taxa de desenvolvimento folicular, a taxa de ovulação do folículo único, a espessura endometrial, a taxa positiva de três linhas de sinal e o nível de hormônio folículo estimulante. CONCLUSÃO O efeito terapêutico do tratamento combinado é melhor do que o citrato de clomifeno isolado no tratamento da SOP.

Expression of mammalian target of rapamycin (mTOR), nuclear factor-κ B (NF-κ B) and sterol regulatory element binding protein 2 (SREBP2) in serum and placentas among gravidas with preeclampsia / 中华围产医学杂志

Objective To investigate the level of mammalian target of rapamycin (mTOR) in serum and the expression of mTOR,nuclear factor-κ B (NF-κ B) and sterol regulatory element binding protein 2 (SREBP2) in placenta among gravidas with preeclampsia.Methods From August 2015 to August 2017,60 gravidas including 40 with severe preeclampsia (SPE) and 20 with mild preeclampsia (MPE) who underwent regular prenatal care and delivered by caesarean section were selected from the Second Xiangya Hospital of Central South University.According to the ratio of 2:1,30 gravidas who delivered through caesarean section due to cephalopelvic disproportion,abnormal fetal position or social factors during the same period were enrolled as the control group.Peripheral blood samples were obtained to determine the concentrations of serum mTOR,high density lipoprotein-cholesterol (HDL-C),low density lipoprotein-cholesterol (LDL-C),triglyceride (TG) and total cholesterol (TC) by enzyme linked immunosorbent assay (ELISA).The expression of mTOR,phospho-mTOR (p-mTOR),NF-κ B and SREBP2 in placenta were measured by Western blot.Clinical datas were statistically analyzed using one-way ANOVA,Bonferroni or Dunnett's T3 test,and Pearson's correlation analysis.Results (1) The serum levels of mTOR and LDL-C in the SPE and MPE group were both higher than that in the control group [mTOR:(11 765.56± 1 698.95) and (8 278.56±1 106.59) vs (4 366.19±716.43) pg/ml;LDL-C:(7.81 ±1.90) and (4.11 ±0.75) vs (2.42±0.45) mmol/L,all P＜0.05].Furthermore the serum levels of mTOR and LDL-C in the SPE group were both higher than those in the MPE group (both P＜0.05).The serum level of HDL-C in the SPE and MPE group were lower than that in the control group [(0.36±0.12) and (0.85±0.11) vs (1.33± 0.16) mmol/L,both P＜0.05],and that in the SPE group was lower than that in the MPE group (P＜0.05).Women in the SPE group showed higher TG level when comparing with the MPE and control group [(46.19± 18.92)vs (35.55±6.54) and (33.24±9.78) nmol/L,both P＜0.05],while the TC levels in the SPE and MPE group were higher than that in the control group[(24.72±7.17) and (21.83±4.19) vs (16.32±3.88) nmol/L,both P＜0.05].(2) The placental expressions of mTOR,p-mTOR,NF-κ B and SREBP2 protein in the SPE and MPE group were higher compared with that in the control group [mTOR:(0.52±0.09) and (0.38±0.08) vs (0.24±0.05);p-mTOR:(0.42±0.08) and (0.26±0.05) vs (0.14±0.03);NF-κ B:(0.58±0.10) and (0.36±0.05) vs (0.21 ± 0.03);SREBP2:(0.52 ± 0.08) and (0.33 ± 0.05) vs (0.20 ± 0.05);all P＜0.05],and those expressions of the SPE group also higher comparing with the MPE group.Otherwise the p-mTOR/mTOR ratios in the SPE group and MPE group were higher than that in the control group [(0.75±0.10) and (0.69±0.14) vs (0.59 ±0.13),both P＜0.05].(3) Pearson's correlation analysis showed that serum level of mTOR and placental expressions of mTOR and p-mTOR in the SPE group were positively correlated with serum LDL-C (r=0.682,0.584 and 0.504,all P＜0.05),TG (r=0.612,0.658 and 0.422,all P＜0.05),while serum level of mTOR and placental expressions of mTOR in the SPE group were positively correlated with TC (r=0.598 and 0.452,all P＜0.05),but were negatively correlated with serum HDL-C (r=-0.375,-0.442 and-0.390,all P＜0.05).The NF-κ B expression in placenta of the SPE group was significantly positively correlated with the mTOR expression in placenta and serum LDL-C (r=0.375 and 0.391,both P＜0.05).Moreover,in the SPE group,the SREBP2 level in placenta was significantly positively correlated with placental expression of mTOR and serum TC level (r=0.364 and 0.392,both P＜0.05).(4) In the MPE group,mTOR level in serum and levels of mTOR and p-mTOR in placenta were significantly positively correlated with serum LDL-C (r=0.813,0.641 and 0.465,all P＜0.05),TG (r=0.646,0.529 and 0.502,all P＜0.05) and TC (r=0.558,0.482 and 0.483,all P＜0.05),while the level of serum mTOR was negatively correlated with the level of serum HDL-C (r=-0.606,P＜0.05).The NF-κ B level in placenta in MPE group was positively correlated with the mTOR in placenta and the serum LDL-C (r=0.458 and 0.595,both P＜0.05),while the SREBP2 level in placenta was significantly positively correlated with mTOR in placenta and serum TC (r=0.580,0.560,respectively;both P＜0.05) in the MPE group.Conclusions mTOR,NF-κ B and SREBP2 may play important roles in the onset and development of preeclampsia by interfering lipid metabolism.

Effect of aerobic exercise on blood lipid of hyperlipidemia rats and its mechanism / 第二军医大学学报

Objective To explore the effect of aerobic exercise on blood lipid of hyperlipidemia rats and its mechanism. Methods A total of 120 healthy male SD rats aged 8 weeks were randomized into normal control group, high-fat diet (HF) group, SBC-115076 group and aerobic exercise group, with 30 rats in each group. The rats in the normal control group were fed with standard diet, and the rats in the other 3 groups were fed with HF to establish hyperlipidemia rat model. The rats in the SBC-115076 group were injected with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor SBC-115076 (8 mg/kg) once a week for 8 weeks, and the rats in the aerobic exercise group underwent swimming without load 6 days a week for 8 weeks. After 8 weeks, the rats were sacrificed and the blood samples were collected to determine the levels of serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Pathological changes of thoracic aorta were observed using H-E staining. The mRNA and protein expression levels of PCSK9, low-density lipoprotein receptor (LDLR) and sterol regulatory element binding protein (SREBP) in the hepatic tissues were detected by quantitative real-time PCR, Western blotting and immunofluorescence. Results Compared with the normal control group, the levels of serum TG, TC and LDL of the rats were significantly higher in the HF group, and the level of HDL was significantly lower (P<0.01). Compared with the HF group, the levels of serum TG, TC and LDL of the rats were significantly lower in the SBC-115076 and aerobic exercise groups, and the level of HDL was significantly higher (P<0.01). In the HF rats, the aortic tunica intima was thickened and endothelial cells were damaged and exfoliated. Compared with the HF group, the aortic intima thickening was reduced and endothelial damage was less in the aerobic exercise group. Compared with the normal control group, the mRNA and protein expression levels of PCSK9, SREBP1 and SREBP2 were significantly higher in the HF group, and the mRNA and protein expression levels of LDLR were significantly lower (P<0.01). Compared with the HF group, the mRNA and protein expression levels of PCSK9, SREBP1 and SREBP2 were significantly lower, and the mRNA and protein expression levels of LDLR were significantly higher (P<0.01). Conclusion Aerobic exercise can down-regulate the expression of TG, TC and LDL, up-regulate the expression of HDL, and alleviate the intimal thickening of aorta. The mechanism may be related to down-regulating the expression of PCSK9 and SREBPs, thus eliminating the inhibition of LDLR.

Srebps: a potential therapeutic target for metabolic diseases / 中国药学杂志

Sterol regulatory element binding proteins (SREBPs) are the major transcription factors regulating cholesterol, fatty acid and triglyceride biosynthesis and control the expression of key genes such as lipogenesis and uptake. In this review, we summarize the processing of SREBPs and their interactions with insulin, cyclic adenosine monophosphate (cAMP), and liver X receptor (LXR) for the synthesis and metabolism of lipid, and combine the latest researches to illustrate the function of SREBPs. These findings suggest that inhibition of SREBPs can be a new strategy for the treatment of metabolic diseases, such as type Ⅱ diabetes, insulin resistance, fatty liver, atherosclerosis and tumors.

Quercetin induces cell death in cervical cancer by reducing O-GlcNAcylation of adenosine monophosphate-activated protein kinase / 대한해부학회지

Hyper-O-GlcNAcylation is a general feature of cancer which contributes to various cancer phenotypes, including cell proliferation and cell growth. Quercetin, a naturally occurring dietary flavonoid, has been reported to reduce the proliferation and growth of cancer. Several reports of the anticancer effect of quercetin have been published, but there is no study regarding its effect on O-GlcNAcylation. The aim of this study was to investigate the anticancer effect of quercetin on HeLa cells and compare this with its effect on HaCaT cells. Cell viability and cell death were determined by MTT and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling assays. O-GlcNAcylation of AMP-activated protein kinase (AMPK) was examined by succinylated wheat germ agglutinin pulldown and immunoprecipitation. Immunofluorescence staining was used to detect the immunoreactivitiy of O-linked N-acetylglucosamine transferase (OGT) and sterol regulatory element binding protein 1 (SREBP-1). Quercetin decreased cell proliferation and induced cell death, but its effect on HaCaT cells was lower than that on HeLa cells. O-GlcNAcylation level was higher in HeLa cells than in HaCaT cells. Quercetin decreased the expression of global O-GlcNAcylation and increased AMPK activation by reducing the O-GlcNAcylation of AMPK. AMPK activation due to reduced O-GlcNAcylation of AMPK was confirmed by treatment with 6-diazo-5-oxo-L-norleucine. Our results also demonstrated that quercetin regulated SREBP-1 and its transcriptional targets. Furthermore, immunofluorescence staining showed that quercetin treatment decreased the immunoreactivities of OGT and SREBP-1 in HeLa cells. Our findings demonstrate that quercetin exhibited its anticancer effect by decreasing the O-GlcNAcylation of AMPK. Further studies are needed to explore how quercetin regulates O-GlcNAcylation in cancer.

Relationship Between Sterol Regulatory Element Binding Protein-1 and Nucleotide-binding Oligomerization Domain-like Receptor Protein-1 Inflammasome in Patients With Coronary Artery Disease / 中国循环杂志

Objective: To study the relationship between sterol regulatory element binding protein-1 (SREBP-1) and nucleotide-binding oligomerization domain-like receptor protein-1 (NLRP-1) inflammasome in patients with coronary artery disease (CAD). Methods: Our research included in 3 groups: Control group, n=20 normal subjects, SAP (stable angina pectoris) group, n=49 and ACS (acute coronary syndrome) group, n=55. Plasma levels of IL-1β, IL-18 and hs-CRP were examined by ELISA, mRNA and protein expressions of SREBP-1, NLRP-1 and Caspase-1 in peripheral blood mononuclear cells (PBMC) were detected by RT-PCR and Western blot analysis. Relationships between SREBP-1 and NLRP1, Caspase-1, IL-1β, IL-18 were studied. Results: Compared with Control group, ACS group and SAP group had increased plasma levels of IL-1β, IL-18 and hs-CRP, all P<0.05; elevated mRNA and protein expressions of SREBP-1, NLRP-1 and Caspase-1 in PBMC, in addition, those expressions in ACS group was even higher than SAP group, all P<0.05. SREBP-1 level was positively related to NLRP1, Caspase-1, IL-1β and IL-18, all P<0.05. Conclusion: The expressions of SREBP-1 and NLRP1 inflammasome were increased in CAD patients; SREBP-1 and NLRP1 had positive correlation.

Role of sterol regulatory element-binding proteins in lipid metabolism-related diseases / 基础医学与临床

Sterol regulatory element-binding proteins(SREBPs),as a major regulator of liposome in vivo,plays an important role in controlling liver lipid synthesis and inducing expression of genes involved in fatty acid,triglyceride and cholesterol synthesis.Part of the traditional Chinese medicine and its derivatives through the SREBP can be tar-get treatment of lipid metabolism related diseases.

Study on the expression of ABCA1,PPAR,SREBP,ADPN and LXR α in patients with type 2 diabetes mellitus / 国际检验医学杂志

Objective To investigate the value of the expression of Adenosine Triphosphate (ATP) binding cassette transporter A1 (ABCA1),peroxisome proliferator activated receptor γ(PPARγ) and sterol regulato-ry element binding protein (SREBP),adiponectin (ADPN) and liver X recepto α(LXRα) in type 2 diabetic pa-tients.Methods 71 patients with type 2 diabetes received in the hospital from June 2015 to June 2017 were se-lected as the observation group,and 60 healthy persons who underwent the health assessment from June 2015 to June 2017 were selected as the control group.Peripheral venous blood was collected from patients with an empty stomach in the morning,serum was isolated and serum human ADPN content were measured by radio-immunoassay.The levels of serum ABCA1,PPAR γ,SREBP and LXR α were measured by Enzyme linked im-munosorbent assay.Results The serum levels of ABCA1 and ADPN in the observation group were lower than those in the control group,while serum PPARγ SREBP and LXRα levels were higher than those in the control group (P< 0.05);the diagnostic sensitivity and specificity of ABCA 1+ PPARγ+ SREBP+ ADPN + LXRα were higher than those of single detection of ABCA1,PPARγ,SREBP,ADPN and LXRα.Conclusion The levels of ABCA1 and ADPN decreased in patients with type 2 diabetes,while the levels of PPAR γ,SREBP and LXR α was increased.The five joint diagnosis of ABCA1+ PPAR γ+SREBP+ADPN+LXR α has high sensitivity and specificity.It was of important clinical value and worth further application.

Hypolipidemic effect of SIPI-7623, a derivative of an extract from oriental wormwood, through farnesoid X receptor antagonism / 中国天然药物

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid and cholesterol metabolism and lipid and glucose homeostasis. Therefore, FXR is a potential drug target for several metabolic syndromes, especially those related to lipidemia disorders. In the present study, we identified small molecule SIPI-7623, a derivative of an extract from Oriental wormwood (Artemisia capillaris), and found that it specifically upregulated the expression of cholesterol-7-alpha-hydroxylase (CYP7A1), downregulated the expression of sterol-regulatory element-binding protein 1c (SREBP-1c) in the liver, and inhibited the expression of ileal bile acid binding-protein (IBABP) in the ileum of rats. We found that inhibition of FXR by SIPI-7623 decreased the level of cholesterol and triglyceride. SIPI-7623 reduced the levels of cholesterol and triglyceride in in vitro HepG2 cell models, ameliorated diet-induced atherosclerosis, and decreased the serum lipid content on rats and rabbits model of atherosclerosis in vivo. Furthermore, SIPI-7623 decreased the extent of atherosclerotic lesions. Our resutls demonstrated that antagonism of the FXR pathway can be employed as a therapeutic strategy to treat metabolic diseases such as hyperlipidemia and atherosclerosis. In conclusion, SIPI-7623 could be a promising lead compound for development of drugs to treat hyperlipidemia and atherosclerosis.

Hypolipidemic effect of SIPI-7623, a derivative of an extract from oriental wormwood, through farnesoid X receptor antagonism / 中国天然药物

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid and cholesterol metabolism and lipid and glucose homeostasis. Therefore, FXR is a potential drug target for several metabolic syndromes, especially those related to lipidemia disorders. In the present study, we identified small molecule SIPI-7623, a derivative of an extract from Oriental wormwood (Artemisia capillaris), and found that it specifically upregulated the expression of cholesterol-7-alpha-hydroxylase (CYP7A1), downregulated the expression of sterol-regulatory element-binding protein 1c (SREBP-1c) in the liver, and inhibited the expression of ileal bile acid binding-protein (IBABP) in the ileum of rats. We found that inhibition of FXR by SIPI-7623 decreased the level of cholesterol and triglyceride. SIPI-7623 reduced the levels of cholesterol and triglyceride in in vitro HepG2 cell models, ameliorated diet-induced atherosclerosis, and decreased the serum lipid content on rats and rabbits model of atherosclerosis in vivo. Furthermore, SIPI-7623 decreased the extent of atherosclerotic lesions. Our resutls demonstrated that antagonism of the FXR pathway can be employed as a therapeutic strategy to treat metabolic diseases such as hyperlipidemia and atherosclerosis. In conclusion, SIPI-7623 could be a promising lead compound for development of drugs to treat hyperlipidemia and atherosclerosis.

SREBP2m promotes proliferation and migration of hepatocarcinoma cells and inhibits apoptosis through cholesterol metabolism damage / 肿瘤

Objective: To investigate the effects of sterol regulatory element binding protein 2 (SREBP2) on the metabolism of cholesterol as well as the proliferation, apoptosis and migration of normal liver LO2 cells and hepatocellular carcinoma HepG2 cells. Methods: By using pAd-Easy-1 adenovirus vector system, the recombinant adenovirus Ad-SREBP2m (carrying the splicing form of SREBP2) and Ad-GFP (as the control) were constructed, and then infected into LO2 and HepG2 cells, respectively. The total cholesterol level in LO2 and HepG2 cells after infection was detected by a cholesterol quantification kit. The expression levels of SREBP2m, cholesterol synthesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and apoptosis-related proteins (including caspase 3, cleaved-caspase 3 and caspase 12) were detected by Western blotting. The effects of Ad-SREBP2m overexpression on the proliferation, cell cycle, apoptosis and migration of LO2 or HepG2 cells were detected by EdU staining method, FCM and scratch wound healing test, respectively. Results: The recombinant adenovirus Ad-SREBP2m was successfully constructed. Compared with the Ad-GFP group, the expression levels of SREBP2m and its target protein HMGCR were up-regulated (both P 0.05); while in HepG2 cells infected with Ad-SREBP2m, the proportion of G1-phase cells decreased significantly (P < 0.001), but the proportion of S-phase cells increased significantly (P < 0.001). SREBP2m overexpression promoted the proliferation of HepG2 cells (P < 0.001), but had no effect on the proliferation of LO2 cells. The expression levels of total caspase 3, cleaved-caspase 3 and caspase 12 were significantly higher in LO2 cells infected with Ad-SREBP2m than those in Ad-GFP group (all P < 0.001), while the expression levels of total caspase 3, cleaved-caspase 3 and caspase 12 were decreased in HepG2 cells infected with Ad-SREBP2m (all P < 0.05). The apoptosis rate of LO2 cells after Ad-SREBP2m infection was increased by (11.40±0.52)% (P < 0.001), while the apoptosis rate of HepG2 cells in Ad-SREBP2m group was decreased by (4.17±0.47)% as compared with Ad-GFP group (P < 0.05). The migration distance of HepG2 cells in Ad-SREBP2m group was (1.17±0.12) mm more than that in Ad-GFP group (P < 0.05). Conclusion: Overexpression of SREBP2m can promote the proliferation and migration and inhibit the apoptosis of hepatocellular carcinoma HepG2 cells, but it can promote apoptosis of normal liver LO2 cells.

Mechanisms of PPARα,sterol regulatory element binding proteins and AMP-activated protein kinase in alcoholic fatty liver diseases:review / 中国药理学与毒理学杂志

Alcoholic fatty liver disease (AFLD) is the first step to wards alcoholic liver disease (ALD). A beffer knowledge of AFLD will contribute to the prevention and therapy of ALD. It has been found that the occurrence and development of AFLD mainly involve the pathways of cytochrome P450 (CYP2E1),peroxisome proliferator-activated receptor α(PPARα),sterol regulatory element-binding proteins (SREBPs),AMP-activated protein kinase(AMPK),sirtuin 1(SIRT1),adiponectin and insulin.This review focuses on the importance of PPARα,SREBPs and AMPK pathway in alcoholic steatosis.It's reported that alcohol and its metabolite acetaldehyde inhibit PPARα and AMPK,and activate SREBP protein directly or indirectly,leading to liver lipid metabolic disorders,reducing the ability of fatty acid oxidation,causing lipid accumulation, and eventually inducing AFLD. Additionally, this review outlines the prospect of a therapeutics of AFLD targetting PPARα,SREBPs and AMPK.