rosmarinic-acid and Non-alcoholic-Fatty-Liver-Disease

Nonalcoholic steatohepatitis (NASH) is considered as a common liver disease. SIRT1, a pivotal sensor, controls activation of metabolic, inflammatory and apoptotic pathways. Rosmarinic acid (RA) has positive effects on the liver injuries; nevertheless, its mechanisms are not completely studied. The aim of this study was to explore the role of rosmarinic acid on the pathways involved by SIRT1 for amelioration of a mouse model of NASH. To do this, C57/BL6 mice were divided into four equal groups (6 in each group). Animals received saline and rosmarinic acid as the control groups. NASH was induced by methionine-choline-deficient (MCD) diet. In the NASH + RA group, Rosmarinic acid was injected daily in mice fed on an MCD diet. Rosmarinic acid decreased plasma triglyceride, cholesterol, liver Steatosis and oxidative stress. Rosmarinic acid administration also increased SIRT1, Nrf2 and PPARα and decreased SREBP1c, FAS, NFκB and caspase3 expressions. Moreover, TNFα, IL6, P53, Bax/Bcl2 ratio and caspase3 expressions decreased. Our study demonstrated that remarkable effects of rosmarinic acid on the mice with NASH might be due to activation of SIRT1/Nrf2, SIRT1/NFκB and SIRT1/PPARα pathways, which alleviate hepatic steatosis, oxidative stress, inflammation and apoptosis.

Topics: Animals; Anti-Inflammatory Agents; Choline; Cinnamates; Depsides; Disease Models, Animal; Liver; Methionine; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; NF-kappa B; Non-alcoholic Fatty Liver Disease; PPAR alpha; Rosmarinic Acid; Sirtuin 1

Rosmarinic acid (RA) is a water-soluble phenolic compound extracted from Boraginaceae and Lamiaceae. This study was designed to investigate the role and mechanism of action of RA in improving nonalcoholic fatty liver disease (NAFLD). Male SD rats maintained on a high fat diet and L02 cells stimulated with oleic acid were treated with RA. Our results showed that RA significantly reduced total cholesterol, triglycerides, low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and malondialdehyde levels and increased high-density lipoprotein cholesterol, superoxide dismutase and adenosine triphosphate levels both in vivo and in vitro. Hematoxylin and eosin staining and oil red O staining showed that RA had a good lipid-lowering effect and substantial protective effects on liver injury. Transmission electron microscopy and JC-1 fluorescence results showed that RA could improve mitochondrial damage in hepatocytes. Additionally, flow cytometry results indicated that RA inhibited ROS generation and apoptosis in L02 cells. The impaired hepatocytes were restored by using RA in NAFLD models characterized by down-regulating YAP1 and TAZ, meanwhile up-regulating PPARγ and PGC-1α. When YAP1 was over-expressed, RA reduced the expression of YAP1; however, the action of RA was significantly blocked by silencing YAP1. The experimental results indicated that RA markedly alleviated NAFLD by repairing mitochondrial damage and regulating the YAP1/TAZ-PPARγ/PGC-1α signaling pathway.

Topics: Animals; Cinnamates; Depsides; Disease Models, Animal; Male; Non-alcoholic Fatty Liver Disease; PPAR gamma; Rats; Rats, Sprague-Dawley; Rosmarinic Acid; Signal Transduction; Transfection

Nonalcoholic fatty liver disease (NAFLD) ranges in severity from hepatic steatosis to cirrhosis. Lemon balm and its major constituent, rosmarinic acid (RA), effectively improve the liver injury and obesity; however, their therapeutic effects on nonalcoholic steatohepatitis (NASH) are unknown. In this study, we investigated the effects of RA and a lemon balm extract (LBE) on NAFLD and liver fibrosis and elucidated their mechanisms. Palmitic acid (PA)-exposed HepG2 cells and db/db mice fed a methionine- and choline-deficient (MCD) diet were utilized to exhibit symptoms of human NASH. LBE and RA treatments alleviated the oxidative stress by increasing antioxidant enzymes and modulated lipid metabolism-related gene expression by the activation of adenosine monophosphate-activated protein kinase (AMPK) in vitro and in vivo. LBE and RA treatments inhibited the expression of genes involved in hepatic fibrosis and inflammation in vitro and in vivo. Together, LBE and RA could improve liver damage by non-alcoholic lipid accumulation and may be promising medications to treat NASH.

Topics: AMP-Activated Protein Kinases; Animals; Cells, Cultured; Cinnamates; Depsides; Disease Models, Animal; Gene Expression; Hep G2 Cells; Humans; Lipid Metabolism; Liver; Male; Melissa; Mice, Inbred Strains; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Phytotherapy; Rosmarinic Acid

Rosmarinus officinalis Linn. is a kind of medicinal and edible homologous plant, which is popular in the Mediterranean region with a significant effect on mind tranquilization, anti-oxidation, and metabolic improvement. However, the hypolipidemic effects and mechanism of rosemary ethanol extract (RO) and their metabolites are less known. In this study, the hypolipidemic effects of RO and its active compounds were clarified. The results showed that RO, rosmarinic acid (RA) and carnosic acid (CA) significantly reduced the contents of liver triglyceride (TG), total cholesterol (TC), free fatty acids (FFA) and improved cell hypertrophy, vacuolation, and cell necrosis in the liver of orotic acid induced non-alcoholic fatty liver disease (NAFLD) model rats. The mechanism and related pathways of RO and its main metabolites against lipid disorder were related to the up-regulation of the phosphorylation of adenosine 5'-monophosphate(AMP)-activated protein kinase (AMPK) and the inhibition of the sterol regulatory element binding protein-1c (SREBP-1c) cracking into the nucleus, following the down-regulation of fatty acid synthesis. In conclusion, our study demonstrates that RA and CA are active substances of RO, and provides scientific evidence to support functional food product development for improving NAFLD.

Topics: Abietanes; Animals; Cinnamates; Depsides; Hep G2 Cells; Humans; Lipid Metabolism; Male; Non-alcoholic Fatty Liver Disease; Orotic Acid; Plant Extracts; Rats; Rats, Sprague-Dawley; Rosmarinic Acid; Rosmarinus