peoniflorin and Fatty-Liver

Diabetic liver injury (DLI) is a complication that damages the quality of life in diabetes patients. While paeoniflorin (PF) exhibits anti-inflammatory and antioxidant effects, no data are available on whether PF protects against DLI. Therefore, we evaluated the effects of PF on hepatic steatosis and inflammation in db/db mice, a type 2 diabetes model.. In this study, we investigated the effects of PF on DLI using diabetic mice model (db/db mice) and high glucose (HG)-induced mouse AML12 cells. The effects of PF on TXNIP-mediated NLRP3 inflammasome in vivo and in vitro were evaluated by Western bloting, RT-PCR, immunohistochemistry (IHC) and immunofluorescence (IF) analysis. Through molecular docking experiments and cellular thermal shift assay (CETSA), we studied the binding ability of PF to thioredoxin-interacting protein (TXNIP). We use TXNIP siRNA to knock down TXNIP in AML12 cells.. We found that PF reversed abnormal liver function and liver steatosis in db/db mice, while blocking the release of inflammatory cytokines. These effects are associated with PF inhibition of the TXNIP/NLRP3 signaling pathway. Molecular docking experiments and CETSA also demonstrated that TXNIP is a likely target of PF. In HG-treated AML12 cells, TXNIP knockdown eliminated the beneficial effects of PF.. Using a combination of animal and in vitro experiments, this study demonstrated for the first time that PF ameliorates DLI through targeting the TXNIP-activated NLRP3 inflammasome. Thus, PF may be a potential therapeutic agent against DLI.

Topics: Animals; Carrier Proteins; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fatty Liver; Glucosides; Inflammasomes; Mice; Molecular Docking Simulation; Monoterpenes; NLR Family, Pyrin Domain-Containing 3 Protein; Reactive Oxygen Species; Thioredoxins

In this study, we evaluated the effects of paeoniflorin (PF) on palmitate (PA)-induced insulin resistance and explored the potential molecular mechanisms in HepG2 cells. HepG2 cells were pre-treated with 3μM, 30μM, or 100μM PF for 1h followed by immediate stimulation with 0.25mM palmitate for 24h to induce hepatic steatosis. PF treatment could decrease PA-induced intracellular lipid deposition via inhibiting de novo lipid synthesis. PF treatment also restored insulin sensitivity by suppressing the activation of Rho kinase (ROCK) and the expression of serine phosphorylation of insulin receptor substrate (IRS)-1, thereby promoting Akt and glycogen synthase kinase (GSK)-3β phosphorylation. These results suggest that PF alleviates PA-induced hepatic steatosis and insulin resistance in HepG2 cells. Furthermore, the effect of PF may be associated with its role in inhibiting de novo lipid synthesis and in regulating the ROCK/IRS/Akt signalling pathways.

Topics: Cell Line, Tumor; Fatty Liver; Glucose; Glucosides; Glycogen Synthase Kinase 3 beta; Hep G2 Cells; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Lipid Metabolism; Lipids; Monoterpenes; Palmitates; Phosphorylation; Proto-Oncogene Proteins c-akt; rho-Associated Kinases; Signal Transduction

BACKGROUND Paeoniflorin is a monoterpene glycoside extracted from the roots of Paeonia lactiflora and is used in Chinese herbal medicine to treat hyperlipidemia. The aim of this study was to evaluate the effects of an enriched extract of paeoniflorin on cholesterol levels, hemodynamics, and oxidative stress in a hyperlipidemic rat model. MATERIAL AND METHODS Male Sprague-Dawley rats were fed high-cholesterol diets and treated with three different doses of paeoniflorin for 12 weeks. The effects of paeoniflorin treatment were assessed on cholesterol levels, cholesterol metabolism, red blood cell vascular flow using hemorheology, antioxidant enzymes, and expression of the rate-limiting enzyme in the mevalonate pathway, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR). Rat liver histology and immunohistochemical analysis were performed to evaluate the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), cytochrome P450 7A1 (CYP7A1), and peroxisome proliferator-activated receptors (PPAR)-α. Protein expression HMG-CoAR, low-density lipoprotein receptor (LDLR), PPAR-α and CYP7A1 was measured by Western blotting. Antioxidant activity in rat liver was determined by measuring superoxide dismutase (SOD) and malondialdehyde (MDA). RESULTS Serum and hepatic cholesterol, hepatic steatosis and the products of cholesterol metabolism were reduced by paeoniflorin treatment, which also reduced the activity of HMG-CoAR and upregulated the expression of LDLR, PPAR-α, and CYP7A1 expression, increased SOD, decreased MDA, and upregulated Nrf2 expression. CONCLUSIONS The findings of this study in a rat model of hyperlipidemia have shown that paeoniflorin regulates hepatic cholesterol synthesis and metabolism and may also protect the liver from oxidative stress.

Topics: Animals; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Diet, High-Fat; Disease Models, Animal; Drugs, Chinese Herbal; Fatty Liver; Glucosides; Glycosides; Hyperlipidemias; Lipid Metabolism; Lipoproteins, LDL; Liver; Male; Monoterpenes; NF-E2-Related Factor 2; PPAR alpha; Rats; Rats, Sprague-Dawley; Triglycerides