Salidroside Activates the AMP-Activated Protein Kinase Pathway to Suppress Nonalcoholic Steatohepatitis in Mice.
AMP-Activated Protein Kinases
/ metabolism
Animals
Cells, Cultured
Diet, High-Fat
/ adverse effects
Disease Models, Animal
Glucosides
/ pharmacology
Hepatocytes
/ drug effects
Humans
Liver
/ drug effects
Male
Mice
Non-alcoholic Fatty Liver Disease
/ drug therapy
Phenols
/ pharmacology
Primary Cell Culture
Signal Transduction
/ drug effects
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
revised:
02
07
2021
received:
03
06
2021
accepted:
07
07
2021
pubmed:
23
7
2021
medline:
15
1
2022
entrez:
22
7
2021
Statut:
ppublish
Résumé
NASH is becoming a leading cause of liver cirrhosis and HCC. Salidroside (p-hydroxyphenethyl-β-D-glucoside; SAL) has various biological and pharmacological activities, including anti-inflammatory, -oxidant, and -cancer activities. However, the therapeutic effect and underlying molecular mechanism of SAL in NASH remain to be further clarified. In this study, we found that SAL alleviated lipid accumulation and inflammatory response in primary hepatocytes after palmitic acid/oleic acid (PO) stimulation. In addition, SAL effectively prevented high-fat/high-cholesterol (HFHC)-diet-induced NASH progression by regulating glucose metabolism dysregulation, insulin resistance, lipid accumulation, inflammation, and fibrosis. Mechanistically, integrated RNA-sequencing and bioinformatic analysis showed that SAL promoted AMPK-signaling pathway activation in vitro and in vivo, and this finding was further verified by determining the phosphorylation levels of AMPK. Furthermore, the protective effects of SAL on lipid accumulation and inflammation in hepatocytes and livers induced by PO or HFHC stimulation were blocked by AMPK interruption. Our studies demonstrate that SAL protects against metabolic-stress-induced NASH progression through activation of AMPK signaling, indicating that SAL could be a potential drug component for NASH therapy.
Sections du résumé
BACKGROUND AND AIMS
NASH is becoming a leading cause of liver cirrhosis and HCC. Salidroside (p-hydroxyphenethyl-β-D-glucoside; SAL) has various biological and pharmacological activities, including anti-inflammatory, -oxidant, and -cancer activities. However, the therapeutic effect and underlying molecular mechanism of SAL in NASH remain to be further clarified.
METHODS AND RESULTS
In this study, we found that SAL alleviated lipid accumulation and inflammatory response in primary hepatocytes after palmitic acid/oleic acid (PO) stimulation. In addition, SAL effectively prevented high-fat/high-cholesterol (HFHC)-diet-induced NASH progression by regulating glucose metabolism dysregulation, insulin resistance, lipid accumulation, inflammation, and fibrosis. Mechanistically, integrated RNA-sequencing and bioinformatic analysis showed that SAL promoted AMPK-signaling pathway activation in vitro and in vivo, and this finding was further verified by determining the phosphorylation levels of AMPK. Furthermore, the protective effects of SAL on lipid accumulation and inflammation in hepatocytes and livers induced by PO or HFHC stimulation were blocked by AMPK interruption.
CONCLUSIONS
Our studies demonstrate that SAL protects against metabolic-stress-induced NASH progression through activation of AMPK signaling, indicating that SAL could be a potential drug component for NASH therapy.
Substances chimiques
Glucosides
0
Phenols
0
AMP-Activated Protein Kinases
EC 2.7.11.31
rhodioloside
M983H6N1S9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3056-3073Informations de copyright
© 2021 by the American Association for the Study of Liver Diseases.
Références
Yu Y, Cai J, She Z, Li H. Insights into the epidemiology, pathogenesis, and therapeutics of nonalcoholic fatty liver diseases. Adv Sci (Weinh) 2019;6:1801585.
Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55:2005-2023.
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011;34:274-285.
Cai J, Zhang XJ, Li H. The role of innate immune cells in nonalcoholic steatohepatitis. Hepatology 2019;70:1026-1037.
Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15:11-20.
Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44:865-873.
Zhang XJ, She ZG, Li H. Time to step-up the fight against NAFLD. Hepatology 2018;67:2068-2071.
Liu Z, Li X, Simoneau AR, Jafari M, Zi X. Rhodiola rosea extracts and salidroside decrease the growth of bladder cancer cell lines via inhibition of the mTOR pathway and induction of autophagy. Mol Carcinog 2012;51:257-267.
Darbinyan V, Kteyan A, Panossian A, Gabrielian E, Wikman G, Wagner H. Rhodiola rosea in stress induced fatigue-a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty. Phytomedicine 2000;7:365-371.
Kim SH, Hyun SH, Choung SY. Antioxidative effects of Cinnamomi cassiae and Rhodiola rosea extracts in liver of diabetic mice. BioFactors 2006;26:209-219.
Lee Y, Jung JC, Jang S, Kim J, Ali Z, Khan IA, Oh S. Anti-inflammatory and neuroprotective effects of constituents isolated from Rhodiola rosea. Evid Based Complement Alternat Med 2013;2013:514049.
Panossian A, Wikman G, Sarris J. Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine 2010;17:481-493.
Gao J, Zhou R, You X, Luo F, He H, Chang X, et al. Salidroside suppresses inflammation in a D-galactose-induced rat model of Alzheimer’s disease via SIRT1/NF-κB pathway. Metab Brain Dis 2016;31:771-778.
Li D, Fu Y, Zhang W, Su G, Liu BO, Guo M, et al. Salidroside attenuates inflammatory responses by suppressing nuclear factor-κB and mitogen activated protein kinases activation in lipopolysaccharide-induced mastitis in mice. Inflamm Res 2013;62:9-15.
Zhu L, Wei T, Gao J, Chang X, He HE, Luo F, et al. The cardioprotective effect of salidroside against myocardial ischemia reperfusion injury in rats by inhibiting apoptosis and inflammation. Apoptosis 2015;20:1433-1443.
Zhang Y, Zhao Q. Salidroside attenuates interleukin-1β-induced inflammation in human osteoarthritis chondrocytes. J Cell Biochem 2019;120:1203-1209.
Zhang L, Yu H, Zhao X, Lin X, Tan C, Cao G, et al. Neuroprotective effects of salidroside against beta-amyloid-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Neurochem Int 2010;57:547-555.
Fan XJ, Wang Y, Wang L, Zhu M. Salidroside induces apoptosis and autophagy in human colorectal cancer cells through inhibition of PI3K/Akt/mTOR pathway. Oncol Rep 2016;36:3559-3567.
Zhao G, Shi A, Fan Z, Du Y. Salidroside inhibits the growth of human breast cancer in vitro and in vivo. Oncol Rep 2015;33:2553-2560.
Song T, Wang P, Li C, Jia LI, Liang Q, Cao Y, et al. Salidroside simultaneously reduces de novo lipogenesis and cholesterol biosynthesis to attenuate atherosclerosis in mice. Biomed Pharmacother 2021;134:111137.
Wang M, Luo L, Yao L, Wang C, Jiang K, Liu X, et al. Salidroside improves glucose homeostasis in obese mice by repressing inflammation in white adipose tissues and improving leptin sensitivity in hypothalamus. Sci Rep 2016;6:25399.
Yang L, Zhou L, Wang X, Wang W, Wang J. Inhibition of HMGB1 involved in the protective of salidroside on liver injury in diabetes mice. Int Immunopharmacol 2020;89(Pt. A):106987.
Xiong Y, Wang Y, Xiong Y, Gao W, Teng L. Salidroside alleviated hypoxia-induced liver injury by inhibiting endoplasmic reticulum stress-mediated apoptosis via IRE1α/JNK pathway. Biochem Biophys Res Comm 2020;529:335-340.
Li HS, Ying H, He ZY. Salidroside and curcumin formula prevents liver injury in nonalcoholic fatty liver disease in rats. Ann Hepatol 2018;17:769-778.
Wang PX, Ji YX, Zhang XJ, Zhao LP, Yan ZZ, Zhang P, et al. Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates. Nat Med 2017;23:439-449.
Zhao GN, Zhang P, Gong J, Zhang XJ, Wang PX, Yin M, et al. Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4. Nat Med 2017;23:742-752.
Ganz M, Szabo G. Immune and inflammatory pathways in NASH. Hepatol Int 2013;7(Suppl. 2):771-781.
Zhou F, Zhou J, Wang W, Zhang XJ, Ji YX, Zhang P, et al. Unexpected rapid increase in the burden of NAFLD in China from 2008 to 2018: a systematic review and meta-analysis. Hepatology 2019;70:1119-1133.
Dou X, Ding Q, Lai S, Jiang F, Song Q, Zhao X, et al. Salidroside alleviates lipotoxicity-induced cell death through inhibition of TLR4/MAPKs pathway, and independently of AMPK and autophagy in AML-12 mouse hepatocytes. J Funct Foods 2020;65:103691.
Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest 2013;123:2764-2772.
Carling D. AMPK signalling in health and disease. Curr Opin Cell Biol 2017;45:31-37.
Boudaba N, Marion A, Huet C, Pierre R, Viollet B, Foretz M. AMPK re-activation suppresses hepatic steatosis but its downregulation does not promote fatty liver development. EBioMedicine 2018;28:194-209.
Ju L, Wen X, Wang C, Wei Y, Peng Y, Ding Y, et al. Salidroside, a natural antioxidant, improves β-cell survival and function via activating AMPK pathway. Front Pharmacol 2017;8:749.
Li HB, Ge YK, Zheng XX, Zhang L. Salidroside stimulated glucose uptake in skeletal muscle cells by activating AMP-activated protein kinase. Eur J Pharmacol 2008;588:165-169.
Zheng T, Yang X, Li W, Wang Q, Chen LI, Wu D, et al. Salidroside attenuates high-fat diet-induced nonalcoholic fatty liver disease via AMPK-dependent TXNIP/NLRP3 pathway. Oxid Med Cell Longev 2018;2018:8597897.
Gui DI, Cui Z, Zhang L, Yu C, Yao D, Xu M, et al. Salidroside attenuates hypoxia-induced pulmonary arterial smooth muscle cell proliferation and apoptosis resistance by upregulating autophagy through the AMPK-mTOR-ULK1 pathway. BMC Pulm Med 2017;17:191.
Zheng T, Yang X, Wu D, Xing S, Bian F, Li W, et al. Salidroside ameliorates insulin resistance through activation of a mitochondria-associated AMPK/PI3K/Akt/GSK3β pathway. Br J Pharmacol 2015;172:3284-3301.
Zhang Y, Meng Q, Sun Q, Xu Z, Zhou H, Wang Y. LKB1 deficiency-induced metabolic reprogramming in tumorigenesis and non-neoplastic diseases. Mol Metab 2021;44:101131.
Lin SC, Hardie DG. AMPK: sensing glucose as well as cellular energy status. Cell Metab 2018;27:299-313.