morin and Non-alcoholic-Fatty-Liver-Disease

The valuable effects of metformin (MET) and morin (MOR) in the improvement of NAFLD have been proposed, nevertheless, their combination impacts were not investigated so far. We determined the therapeutic effects of combined MET and MOR treatment in high-fat diet (HFD)-induced Non-alcoholic fatty liver disease (NAFLD) mice.. C57BL/6 mice were fed on an HFD for 15 weeks. Animals were allotted into various groups and supplemented with MET (230 mg/kg), MOR (100 mg/kg), and MET + MOR (230 mg/kg + 100 mg/kg).. MET in combination with MOR reduced body and liver weight in HFD-fed mice. A significant decrease in fasting blood glucose and improvement in glucose tolerance was observed in HFD mice treated with MET + MOR. Supplementation with MET + MOR led to a decline in hepatic triglyceride levels and this impact was associated with diminished expression of fatty-acid synthase (FAS) and elevated expression of carnitine palmitoyl transferase 1 (CPT1) and phospho-Acetyl-CoA Carboxylase (p-ACC). Moreover, MET combined with MOR alleviates hepatic inflammation through the polarization of macrophages to the M2 phenotype, decreasing the infiltration of macrophages and lowering the protein level of NF-kB. MET and MOR in combination reduce the size and weight of epididymal white adipose tissue (eWAT), and subcutaneous WAT (sWAT), whereas improves cold tolerance, BAT activity, and mitochondrial biogenesis. Combination therapy results in stimulating brown-like adipocyte (beige) formation in the sWAT of HFD mice.. These results suggest that the combination of MET and MOR has a protective effect on hepatic steatosis, which may use as a candidate therapeutic for the improvement of NAFLD.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Diet, High-Fat; Inflammation; Lipid Metabolism; Metformin; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Thermogenesis

Morin (MO), a natural bioflavinoid, exists in many herbs. Previous studies have acclaimed MO's anti-inflammatory, antidiabetic, antioxidant, antifibrotic, anticancer, and antihyperglycemic biological effects. This study aimed to assess the molecular mechanism of MO involved in the oleic acid (OA)-induced inflammatory damage and lipid accumulation in HepG2 cell and tyloxapol (Ty)-induced hyperlipidemia in mice. We found that MO can efficaciously mitigate reactive tumor necrosis factor-α (TNF-α) level and triglyceride (TG) accumulation in OA-induced HepG2 cell and in tyloxapol-induced mice. Next, the study testified that MO apparently suppressed OA-excited nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways in HepG2 cell. In addition, MO distinctly upregulated the expression of peroxisome proliferator-activated receptor α (PPARα) and decreased the expression of sterol regulatory element-binding protein 1c (SREBP-1c) in OA-induced HepG2 cell and in tyloxapol-induced mice, both of which are dependent upon the phosphorylation of acetyl-CoA carboxylase (ACC), adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and protein kinase B (AKT). In conclusion, these results suggest that MO has protective potential against hyperlipidemia and steatosis, and the potential mechanism may have a close relation with activation of PPARα and inhibition of SREBP-1c.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinase Kinases; Animals; Flavonoids; Hep G2 Cells; Hepatocytes; Humans; Hyperlipidemias; Inflammation; Lipid Metabolism; Mice; Non-alcoholic Fatty Liver Disease; Oleic Acid; Phosphorylation; Polyethylene Glycols; PPAR alpha; Protein Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Triglycerides

Morin is a natural occurring flavonoid in many dietary plants and has a wide range of beneficial effects on metabolism; however, the mechanism underlying its action remains elusive.. A reporter assay and the time-resolved FRET assay were used to identify morin as a dual antagonist of liver X receptor (LXR)-α and -β. Morin (100 mg. From the in vitro assays, morin was shown to be a dual antagonist of LXRα and LXRβ. In vivo, morin blunted the development of liver hepatic steatosis, reduced body weight gains, lowered triglyceride levels and improved glucose and insulin tolerance in mice fed a high-fat diet. Mechanistically, morin inhibited 3T3-L1 adipocyte differentiation and lipid formation in human hepatic HepG2 cells and suppressed the mRNA expression of genes downstream of LXR. Consistently, the effects of morin on metabolic disorders were attenuated in LXRβ. Our data reveal that morin is a dual antagonist of LXRα and LXRβ and suggest that morin may alleviate hepatic steatosis and other associated metabolic disorders via the suppression of LXR signalling and, therefore, shows promise as a novel therapy or nutraceutical for nonalcoholic fatty liver disease.

Topics: 3T3-L1 Cells; Animals; Cells, Cultured; Dose-Response Relationship, Drug; Female; Flavonoids; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Structure; Non-alcoholic Fatty Liver Disease; Structure-Activity Relationship