Oxidative stress is a critical factor in nonalcoholic fatty liver disease pathogenesis. MicroRNA-200a (miR-200a) is reported to target Kelch-like ECH-associated protein 1 (Keap1), which regulates nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant pathway. Polydatin (3,4',5-trihydroxy-stilbene-3-β-D-glucoside), a polyphenol found in the rhizome of Polygonum cuspidatum, have anti-oxidative, anti-inflammatory and anti-hyperlipidemic effects. However, whether miR-200a controls Keap1/Nrf2 pathway in fructose-induced liver inflammation and lipid deposition and the blockade of polydatin are still not clear. Here, we detected miR-200a down-regulation, Keap1 up-regulation, Nrf2 antioxidant pathway inactivation, ROS-driven thioredoxin-interacting protein (TXNIP) over-expression, NOD-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome activation and dysregulation of peroxisome proliferator activated receptor-α (PPAR-α), carnitine palmitoyl transferase-1 (CPT-1), sterol regulatory element binging protein 1 (SREBP-1) and stearoyl-CoA desaturase-1 (SCD-1) in rat livers, BRL-3A and HepG2 cells under high fructose induction. Furthermore, the data from the treatment or transfection of miR-200a minic, Keap1 and TXNIP siRNA, Nrf2 activator and ROS inhibitor demonstrated that fructose-induced miR-200a low-expression increased Keap1 to block Nrf2 antioxidant pathway, and then enhanced ROS-driven TXNIP to activate NLRP3 inflammasome and disturb lipid metabolism-related proteins, causing inflammation and lipid deposition in BRL-3A cells. We also found that polydatin up-regulated miR-200a to inhibit Keap1 and activate Nrf2 antioxidant pathway, resulting in attenuation of these disturbances in these animal and cell models. These findings provide a novel pathological mechanism of fructose-induced redox status imbalance and suggest that the enhancement of miR-200a to control Keap1/Nrf2 pathway by polydatin is a therapeutic strategy for fructose-associated liver inflammation and lipid deposition.

High fructose intake is a risk factor for liver fibrosis. Polydatin is a main constituent of the rhizome of Polygonum cuspidatum, which has been used in traditional Chinese medicine to treat liver fibrosis. However, the underlying mechanisms of fructose‐driven liver fibrosis as well as the actions of polydatin are not fully understood. In this study, fructose was found to promote zinc finger E‐box binding homeobox 1 (ZEB1) nuclear translocation, decrease microRNA‐203 (miR‐203) expression, increase survivin, activate transforming growth factor β1 (TGF‐β1)/Smad signalling, down‐regulate E‐cadherin, and up‐regulate fibroblast specific protein 1 (FSP1), vimentin, N‐cadherin and collagen I (COL1A1) in rat livers and BRL‐3A cells, in parallel with fructose‐induced liver fibrosis. Furthermore, ZEB1 nuclear translocation‐mediated miR‐203 low‐expression was found to target survivin to activate TGF‐β1/Smad signalling, causing the EMT in fructose‐exposed BRL‐3A cells. Polydatin antagonized ZEB1 nuclear translocation to up‐regulate miR‐203, subsequently blocked survivin‐activated TGF‐β1/Smad signalling, which were consistent with its protection against fructose‐induced EMT and liver fibrosis. These results suggest that ZEB1 nuclear translocation may play an essential role in fructose‐induced EMT in liver fibrosis by targeting survivin to activate TGF‐β1/Smad signalling. The suppression of ZEB1 nuclear translocation by polydatin may be a novel strategy for attenuating the EMT in liver fibrosis associated with high fructose diet.

The high levels of bile acids are a critical factor in hepatorenal syndrome. Organic solute transporter α/β (Ostα/β) participate in bile acids reabsorption in the kidney. Fucoidan has the great potential in protecting against liver and kidney injury. However, whether Ostα/β increase bile acids reabsorption in bile duct ligature (BDL)-induced hepatorenal syndrome and the blockade of fucoidan are still not clear. Male mice that received BDL were given to fucoidan (at 12.5, 25 and 50 ​mg/kg) through intraperitoneal injection once daily for three weeks. The serum, liver and kidney samples of these experimental mice were collected to carry out biochemical, pathological and Western blot analysis. In this study, fucoidan significantly lowered serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), decreased serum levels of uric acid, creatinine and uric nitrogen, restored the deregulation of the renal urate transporter 1 (URAT1), organic anion transporter 1 (OAT1), and organic cation/carnitine transporter 1/2 (OCTN1/2), consistence with alleviation BDL-induced liver and kidney dysfunction, inflammation and fibrosis in mice. Furthermore, fucoidan significantly hampered Ostα/β and reduced bile acids reabsorption in BDL-induced mice, protected against AML12 and HK-2 ​cells injury in vitro. These results demonstrate that fucoidan alleviates BDL-induced hepatorenal syndrome through inhibition Ostα/β to reduce bile acids reabsorption in mice. Therefore, suppression of Ostα/β by fucoidan may be a novel strategy for attenuating hepatorenal syndrome.

Liver disease is a serious threat to health worldwide. Flavonoids from Suaeda glauca (SGF) is able to alleviate liver lipid peroxidation. However, it is unclear whether SGF could protect against liver glycogen accumulation, inflammation and fibrosis. In this study, the extraction conditions of SGF were optimized with response surface methodology. The qualitative analysis of components in SGF was carried out by a LC-MS/MS method. Moreover, SGF was administered orally to male mice given 10 % carbon tetrachloride (CCl₄) for 4 weeks at doses of 25 and 50 mg/kg once daily for 4 weeks. The optimal extraction conditions of SGF were as follows: the ratio of material to liquid 1:35, the temperature 67 °C, the time 3 h, and the ethanol concentration 89 %. Thirty-five compounds were preliminarily identified in SGF. Furthermore, SGF could significantly improve liver dysfunction, regulate the hepatic protein levels of glucose-6-phosphatase, glycogen synthase, glycogen phosphorylase L, Laforin, interleukin-1β, gasdermin-D, NOD-like receptor (NLR) family, pyrin domain containing 3 inflammasome, α-smooth muscle actin, the hepatic mRNA levels and enzyme activities of matrix metallopeptidase 9, tissue inhibitor of metalloproteinases 1, and collagen 1α1, reduce the liver glycogen accumulation, inflammation and fibrosis in mice induced by CCl₄. These results indicated that SGF may be a promising drug for the treatment of liver injury.

Hepatocyte damage is the initial factor in liver injury. De novo expression of inositol 1,4,5-triphosphate receptor type 3 (ITPR3) typically occurs in hepatocellular carcinoma and may contribute to its pathogenesis. However, the role of de novo expression of ITPR3 by hepatocytes in the pathological processes of liver fibrosis remains unclear. Expression analyses of ITPR3 in hepatocytes were combined with an evaluation Ca²⁺/nuclear factor-κB (NF-κB)/leukocyte cell-derived chemotaxin 2 (LECT2) pathway and characterization of the effect of ITPR3 expression on hepatocytes damage. The effect of ITPR3 expression on liver fibrosis were evaluated in mice. ITPR3 expression was significantly increased in fibrotic mice livers and in hepatocytes induced by carbon tetrachloride (CCl₄), correlating with hepatocytes apoptosis. Data from treatment with ITPR3 siRNA and an NF-κB inhibitor demonstrated that excessive Ca²⁺ release mediated by ITPR3 activated NF-κB, which in turn initiated LECT2 expression and induced hepatocytes apoptosis, leading to hepatic stellate cell activation-mediated liver fibrosis. These results demonstrate that de novo expression of ITPR3 may play an essential role in hepatocytes damage and liver fibrosis via Ca²⁺/NF-κB/LECT2 pathway. Suppression of ITPR3 may represent a novel strategy for attenuating hepatocyte damage and liver fibrosis.