OECTIVE Baicalin is a major flavonoid component of Scutellaria baicalensis,and has been used in the treatment of liver diseases for many years.However,the role of baicalin in estrogen-induced cholestasis(EIC)remains t...OECTIVE Baicalin is a major flavonoid component of Scutellaria baicalensis,and has been used in the treatment of liver diseases for many years.However,the role of baicalin in estrogen-induced cholestasis(EIC)remains to be elucidated.This present study explored the protective effect of baicalin against estrogen-induced liver injury and further elucidated the mechanisms involved both in vivo and in vitro.METHODS We conducted a series of experiments using 17α-ethinylestradiol(EE)induced cholestatic rats and cultured HepG2 cells.Serum,bile,and liver samples were collected for biochemical and histological analyses.Bile acid composition in liver was analyzed by LC-MS/MS.The mechanisms underlying the hepatoprotective of baicalin were investigated by RT-PCR,Western blotting analyses and immunohistochemistry.RESULTS Baicalin showed obvious hepatoprotective effects in EIC rats by reducing serum biomarkers and increasing the bile flow rate,as well as by alleviating liver histology and restoring the abnormal composition of hepatic bile acids(BAs).In addition,baicalin protected against EE induced liver injury by up-regulation of the expression of hepatic efflux transporters and down-regulation of hepatic uptake transporters.Furthermore,baicalin increased the expression of hepatic BA synthase(CYP27A1)and metabolic enzymes(Bal,Baat and Sult2a1)in EIC rats.We showed that baicalin significantly inhibited hepatic inflammatory responses in EIC rats through reducing elevated levels of TNF-α,IL^(-1)β,IL-6 and NF-κB.Finally,we confirmed that baicalin maintains BA homeostasis and alleviates inflammation through Sirt1/HNF-1α/FXR signaling pathway.CONCLUSION Baicalin protects against estrogen-induced cholestatic liver injury,and the underlying mechanism involved is related to activation of the Sirt1/HNF-1α/FXR signaling pathway.展开更多
The present review focuses on the roles and underlying mechanisms of action of hepatic nuclear factor-1(HNF-1)in lipid metabolism and the development of lipid metabolism disorders.HNF-1 is a transcriptional regulator ...The present review focuses on the roles and underlying mechanisms of action of hepatic nuclear factor-1(HNF-1)in lipid metabolism and the development of lipid metabolism disorders.HNF-1 is a transcriptional regulator that can form homodimers,and the HNF-1αand HNF-1βisomers can form heterodimers.Both homo-and heterodimers recognize and bind to specific cis-acting elements in gene promoters to transactivate transcription and to coordinate the expression of target lipid-related genes,thereby influencing the homeostasis of lipid metabolism.HNF-1 was shown to restrain lipid anabolism,including synthesis,absorption,and storage,by inhibiting the expression of lipogenesis-related genes,such as peroxisome proliferator-activated receptorγ(PPARγ)and sterol regulatory element-binding protein-1/2(SREBP-1/2).Moreover,HNF-1 enhances the expression of various genes,such as proprotein convertase subtilisin/kexin type 9(PCSK9),glutathione peroxidase 1(GPx1),and suppressor of cytokine signaling-3(SOCS-3)and negatively regulates signal transducer and activator of transcription(STAT)to facilitate lipid catabolism in hepatocytes.HNF-1 reduces hepatocellular lipid decomposition,which alleviates the progression of nonalcoholic fatty liver disease(NAFLD).HNF-1 impairs preadipocyte differentiation to reduce the number of adipocytes,stunting the development of obesity.Furthermore,HNF-1 reduces free cholesterol levels in the plasma to inhibit aortic lipid deposition and lipid plaque formation,relieving dyslipidemia and preventing the development of atherosclerotic cardiovascular disease(ASCVD).In summary,HNF-1 transcriptionally regulates lipid-related genes to manipulate intracorporeal balance of lipid metabolism and to suppress the development of lipid metabolism disorders.展开更多
文摘OECTIVE Baicalin is a major flavonoid component of Scutellaria baicalensis,and has been used in the treatment of liver diseases for many years.However,the role of baicalin in estrogen-induced cholestasis(EIC)remains to be elucidated.This present study explored the protective effect of baicalin against estrogen-induced liver injury and further elucidated the mechanisms involved both in vivo and in vitro.METHODS We conducted a series of experiments using 17α-ethinylestradiol(EE)induced cholestatic rats and cultured HepG2 cells.Serum,bile,and liver samples were collected for biochemical and histological analyses.Bile acid composition in liver was analyzed by LC-MS/MS.The mechanisms underlying the hepatoprotective of baicalin were investigated by RT-PCR,Western blotting analyses and immunohistochemistry.RESULTS Baicalin showed obvious hepatoprotective effects in EIC rats by reducing serum biomarkers and increasing the bile flow rate,as well as by alleviating liver histology and restoring the abnormal composition of hepatic bile acids(BAs).In addition,baicalin protected against EE induced liver injury by up-regulation of the expression of hepatic efflux transporters and down-regulation of hepatic uptake transporters.Furthermore,baicalin increased the expression of hepatic BA synthase(CYP27A1)and metabolic enzymes(Bal,Baat and Sult2a1)in EIC rats.We showed that baicalin significantly inhibited hepatic inflammatory responses in EIC rats through reducing elevated levels of TNF-α,IL^(-1)β,IL-6 and NF-κB.Finally,we confirmed that baicalin maintains BA homeostasis and alleviates inflammation through Sirt1/HNF-1α/FXR signaling pathway.CONCLUSION Baicalin protects against estrogen-induced cholestatic liver injury,and the underlying mechanism involved is related to activation of the Sirt1/HNF-1α/FXR signaling pathway.
基金supported by the National Natural Sciences Foundation of China(No.81770460)the Natural Science Foundation of Guangxi Zhuang Autonomous Region,China(No.2019JJA140728)+2 种基金Scientific Research Foundation for the Excellent Youth of the Education Department of Hunan Province(No.18B264)Aid Program(No.2017KJ268)Key Lab for Clinical Anatomy&Reproductive Medicine(No.2017KJ182)of the Science and Technology Bureau of Hengyang City,China.
文摘The present review focuses on the roles and underlying mechanisms of action of hepatic nuclear factor-1(HNF-1)in lipid metabolism and the development of lipid metabolism disorders.HNF-1 is a transcriptional regulator that can form homodimers,and the HNF-1αand HNF-1βisomers can form heterodimers.Both homo-and heterodimers recognize and bind to specific cis-acting elements in gene promoters to transactivate transcription and to coordinate the expression of target lipid-related genes,thereby influencing the homeostasis of lipid metabolism.HNF-1 was shown to restrain lipid anabolism,including synthesis,absorption,and storage,by inhibiting the expression of lipogenesis-related genes,such as peroxisome proliferator-activated receptorγ(PPARγ)and sterol regulatory element-binding protein-1/2(SREBP-1/2).Moreover,HNF-1 enhances the expression of various genes,such as proprotein convertase subtilisin/kexin type 9(PCSK9),glutathione peroxidase 1(GPx1),and suppressor of cytokine signaling-3(SOCS-3)and negatively regulates signal transducer and activator of transcription(STAT)to facilitate lipid catabolism in hepatocytes.HNF-1 reduces hepatocellular lipid decomposition,which alleviates the progression of nonalcoholic fatty liver disease(NAFLD).HNF-1 impairs preadipocyte differentiation to reduce the number of adipocytes,stunting the development of obesity.Furthermore,HNF-1 reduces free cholesterol levels in the plasma to inhibit aortic lipid deposition and lipid plaque formation,relieving dyslipidemia and preventing the development of atherosclerotic cardiovascular disease(ASCVD).In summary,HNF-1 transcriptionally regulates lipid-related genes to manipulate intracorporeal balance of lipid metabolism and to suppress the development of lipid metabolism disorders.
