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Objectives: Nonalcoholic fatty liver (NAFLD), a chronic progressive liver disease, is highly correlated with pathoglycemia, dyslipidemia and oxidative stress. The free fatty acid receptor 1 (FFA1) agonists have been reported to improve liver steatosis and fibrosis, and the peroxisome proliferator-activated receptor δ (PPARδ) plays a synergistic role with FFA1 in energy metabolism and fibrosis. HWL-088, a PPARδ/FFA1 dual agonist, exerts better glucose-lowering effects than the representative FFA1 agonist TAK-875. However, the ability of HWL-088 to protect NAFLD was unknown. This study aimed to discover a new strategy for the treatment of NAFLD., Methods: The methionine- and choline-deficient diet (MCD)-induced Nonalcoholic steatohepatitis (NASH) model was constructed to evaluate the effects of HWL-088., Key Findings: Administration of HWL-088 exerted multiple benefits on glucose control, lipid metabolism and fatty liver. Further mechanism research indicated that HWL-088 promotes lipid metabolism by decreasing lipogenesis and increasing lipolysis. Moreover, HWL-088 attenuates NASH by regulating the expression levels of genes related to inflammation, fibrosis and oxidative stress., Conclusions: These positive results indicated that PPARδ/FFA1 dual agonist HWL-088 might be a potential candidate to improve multiple pathogenesis of NASH., (© 2020 Royal Pharmaceutical Society.)

We tested the hypothesis that α-lactalbumin inhibits the disruption of intestinal barrier function and liver cirrhosis by restoring gut-liver axis function in thioacetamide (TAA) -treated rats. Rat diets were supplemented with α-lactalbumin replacing 50% of dietary protein. After consuming α-lactalbumin for one week, rats were intraperitoneally injected with TAA twice a week for 14 weeks. The α-lactalbumin-enriched diet significantly inhibited the elevation of plasma alanine aminotransferase, aspartate aminotransferase, and hyaluronic acids. The supplement significantly reduced plasma lipopolysaccharide levels and increased occludin mRNA level. Hepatic fibrosis and regenerative nodules was developed and intestinal villi were shortened by TAA; α-Lactalbumin attenuated these histopathological changes. These results indicated that α-lactalbumin improved intestinal barrier function, suppressing endotoxin levels. These data also suggested that α-lactalbumin ameliorated the impairment of the gut-liver axis by TAA, inhibiting the development of liver cirrhosis.

The Nrf2 pathway protects against oxidative stress and induces regeneration of various tissues. Here, we investigated whether Nrf2 protects from sclerosing cholangitis and biliary fibrosis and simultaneously induces liver regeneration. Diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was fed to Nrf2-KO mice (Nrf2-/-), mice with liver-specific hyperactivated Nrf2 (HKeap1-/-) and wild-type (WT) littermates to induce cholangitis, liver fibrosis, and oval cell expansion. HKeap1-/--mice were protected from almost all DDC-induced injury compared with WT and Nrf2-/-. Liver injury in Nrf2-/- and WT mice was mostly similar, albeit Nrf2-/- suffered more from DDC diet as seen for several parameters. Nrf2 activity was especially important for the expression of the hepatic efflux transporters Abcg2 and Abcc2-4, which are involved in hepatic toxin elimination. Surprisingly, cell proliferation was more enhanced in Nrf2-/-- and HKeap1-/--mice compared with WT. Interestingly, Nrf2-/--mice failed to sufficiently activate oval cell expansion after DDC treatment and showed almost no resident oval cell population under control conditions. The resident oval cell population of untreated HKeap1-/--mice was increased and DDC treatment resulted in a stronger oval cell expansion compared with WT. We provide evidence that Nrf2 activation protects from DDC-induced sclerosing cholangitis and biliary fibrosis. Moreover, our data establish a possible role of Nrf2 in oval cell expansion., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Our previous studies showed the possibility that activation of the antioxidative function alleviates various oxidative damages, which are related to lifestyle diseases. Results showed that, low-dose X-ray irradiation activated superoxide dismutase and inhibits oedema following ischaemia-reperfusion. To alleviate ischaemia-reperfusion injury with transplantation, the changes of the antioxidative function in liver graft using low-dose X-ray irradiation immediately after exenteration were examined. Results showed that liver grafts activate the antioxidative function as a result of irradiation. In addition, radon inhalation enhances the antioxidative function in some organs, and alleviates alcohol-induced oxidative damage of mouse liver. Moreover, in order to determine the most effective condition of radon inhalation, mice inhaled radon before or after carbon tetrachloride (CCl(4)) administration. Results showed that radon inhalation alleviates CCl(4)-induced hepatopathy, especially prior inhalation. It is highly possible that adequate activation of antioxidative functions induced by low-dose irradiation can contribute to preventing or reducing oxidative damages, which are related to lifestyle diseases.

Objectives: The study was to investigate the prevention effects and possible mechanism of Yu Ping Feng San fractioned polysaccharide (YPF-P) on CCl(4)-induced liver fibrosis in rats., Methods: YPF-P was prepared from root of Astragalus membranaceus, rhizome of Atractylodes macrocephaia and root of Raidix saposhnikoviae, and compared with polysaccharide from root of Astragalus membranaceus (AP). Hepatic fibrosis was induced by subcutaneous injection with carbon tetrachloride twice weekly for 12 weeks in Sprague-Dawley rats. YPF-P, AP and colchicine were administered intragastrically daily to carbon tetrachloride-treated rats. Histopathological changes of the liver and hepatic stellate cells were evaluated by Masson staining and transmission electron microscopy, respectively. Markers of fibrosis were determined by radioimmunoassay, biochemistry assay and ELISA. The mRNA expressions of tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-13 (MMP-13), procollagen I and collagen III were detected by RT-PCR., Key Findings: YPF-P dose-dependently alleviated the degree of liver fibrosis and inhibited hepatic stellate cell transformation into myofibroblast-like cells, markedly reduced the elevated levels of hyaluronic acid, laminin, type IV collagen, type III procollagen, hydroxyproline and transforming growth factor beta-1, suppressed procollagen I, collagen III and TIMP-1 expression, and improved the TIMP-1/MMP-13 ratio. MMP-13 expression was only promoted moderately by YPF-P. Compared with AP, YPF-P showed more potency on most markers except laminin, type IV collagen and MMP-13 mRNA., Conclusions: YPF-P prevented the progress of rat liver fibrosis induced by carbon tetrachloride and had a more potent preventative effect. The preventative effect may be associated with the ability of YPF-P to inhibit the synthesis of matrix collagen and balance the TIMP/MMP system.

Objectives: It was found that total flavonoids from Litsea coreana Levl. (TFLC), which is a traditional Chinese medicine, had a preventive effect against hepatic steatosis in our previous study. This study was designed to evaluate whether TFLC could improve liver fibrosis in rats., Methods: The liver fibrosis model rats were treated with composite factors of high-fat emulsion (10 ml/kg) via gavage accompanied by a subcutaneous injection of low-dose CCl(4). Thirty rats were given composite factors plus TFLC (100, 200, 400 mg/kg), respectively, for 8 weeks., Key Findings: The results showed that TFLC (200 and 400 mg/kg) treatment significantly reduced the elevation of liver index (liver weight/body weight) and spleen index (spleen weight/body weight), alanine transaminase, aspartate aminotransferase, hyaluronic acid, laminin, procollagen III N-terminal peptide, procollagenase IV and hydroxyproline. In addition, TFLC treatment improved the morphologic changes of hepatic fibrosis, suppressed expression of alpha-smooth muscle actin, collagen I, transforming growth factor (TGF)-beta1 and TGFbeta receptor (TGFbetaR)1, and increased peroxisome proliferator-activated receptor-gamma expression in the liver of hepatic fibrosis rats., Conclusions: In conclusion, TFLC is able to ameliorate liver injury and protect rats from liver fibrosis. This process may be related to inhibiting the expression of transforming growth factor-beta1 and increasing the expression of peroxisome proliferator-activated receptor-gamma.

Objectives: Non-alcoholic steatohepatitis is associated with the deposition of lipid droplets in the liver, and is characterised histologically by the infiltration of inflammatory cells, hepatocellular degeneration and liver fibrosis. Oxidative stress may play an important role in the onset and deterioration of non-alcoholic steatohepatitis. We previously reported that an Eriobotrya japonica seed extract, extracted in 70% ethanol, exhibited antioxidant actions in vitro and in vivo. In this study, we examined the effect of this extract in a rat model of non-alcoholic steatohepatitis., Methods: The seed extract was given in the drinking water to fats being fed a methionine-choline-deficient diet for 15 weeks., Key Findings: Increases in alanine aminotransferase and aspartate aminotransferase levels were significantly inhibited in rats fed the seed extract compared with the group on the diet alone. Formation of fatty droplets in the liver was also inhibited. Antioxidant enzyme activity in liver tissue was higher than in the diet-only group and lipid peroxidation was reduced compared with rats that also received the extract. Expression of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal was lower in the rats given the seed extract than in the diet-only group. In the former, liver tissue levels of transforming growth factor-beta and collagen were also decreased., Conclusions: Thus, the E. japonica seed extract inhibited fatty liver, inflammation and fibrosis, suggesting its usefulness in the treatment of non-alcoholic steatohepatitis.

The purpose of this study was to investigate the hepatoprotective effects of a fermented substance from Aspergillus phoenicis (FSAP) on chronic liver injuries induced by carbon tetrachloride (CCl(4)) in rats. CCl(4) (20%; 0.2 ml/100 g body weight) was given twice a week for 9 weeks, and the rats received FSAP throughout the whole experimental period. Plasma ALT and AST, spleen weight, and hepatic levels of lipid peroxidation and hydroxyproline were significantly lower in the rats treated with FSAP as compared to CCl(4) only. Liver pathology in the FSAP-treated rats was also improved. Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) analysis showed that FSAP treatment increased the expression of matrix metalloproteinase 13 and decreased the expression of methionine adenosyltransferase 2A, collagen (alpha1)(I), collagen (alpha1)(III), transforming growth factor-beta1, and tissue inhibitor of metalloproteinase 1. These results clearly indicate that FSAP partially reduced the liver fibrosis in rats induced by CCl(4).

Apoptosis is one of the events that are involved in liver fibrogenesis. Thus, factors that affect apoptosis may be used to modulate liver fibrosis. We have recently reported that Salvia miltiorrhiza plays a protective role in carbon tetrachloride (CCl4)-induced hepatic fibrosis. In this study, we aimed to evaluate whether S. miltiorrhiza modulated CCl4-induced hepatic apoptosis in rats. Male Wistar rats were given orally either vehicle or water-extract of S. miltiorrhiza (50 mg kg(-1) twice daily) for nine weeks beginning from the start of CCl4 administration. A group of normal rats was included for comparison. Hepatocyte DNA fragmentation and cytosolic caspase-3 and caspase-8 activity were determined in the experimental animals. Hepatic cytosolic Bax, Bcl-2, cytochrome c, and calpain-mu expressions were measured by Western blot analysis. Hepatic mitochondrial glutathione levels were assessed by colorimetric assay. Compared with normal rats, rats receiving CCl4 alone showed profound DNA fragmentation associated with an increased cytosolic fraction of cytochrome c and calpain-mu protein expressions and a decreased mitochondrial glutathione level. In contrast, a decreased laddering of DNA fragmentation was noted in rats receiving CCl4 plus S. miltiorrhiza extract. The mitochondrial glutathione level was significantly increased in rats receiving CCl4 plus S. miltiorrhiza extract compared with those receiving CCl4 alone. Additionally, cytosolic caspase-3 activity and cytosolic fractions of Bax, Bcl-2, cytochrome c, and calpain-mu protein expressions were decreased in rats receiving CCl4 plus S. miltiorrhiza extract compared with those receiving CCl4 alone. The cytosolic caspase-8 activity in rats receiving CCl4 alone was no different from those receiving CCl4 plus S. miltiorrhiza extract. These results indicated that chronic administration of S. miltiorrhiza ameliorated CCl4-mediatd hepatic apoptosis in rats. This effect may be related to the antioxidant properties of S. miltiorrhiza.

Quercetin, one of the most abundant flavonoids in human diet has been reported to exhibit a wide range of pharmacological properties. In this study, we investigated the protective effect of quercetin on hepatic injury induced by dimethylnitrosamine (DMN) in rats. Treatment with DMN caused a significant decrease in body and liver weight. Oral administration of quercetin (10 mg kg(-1) daily for 4 weeks) remarkably prevented this DMN-induced loss in body and liver weight and inhibited the elevation of serum alanine transaminase, aspartate transaminase and bilirubin levels. Quercetin also increased serum albumin and hepatic glutathione levels and reduced the hepatic level of malondialdehyde. Furthermore, DMN-induced elevation of hydroxyproline content was reduced in the quercetin treated rats, the result of which was consistent with a reduction in type I collagen mRNA production and histological analysis of liver tissue stained with Sirius red. A reduction in hepatic stellate cell activation, as assessed by alpha-smooth muscle actin staining, was associated with quercetin treatment as well as a reduction in transforming growth factor-beta1 expression. In conclusion, these results demonstrate that quercetin exhibited in-vivo hepatoprotective and anti-fibrogenic effects against DMN-induced liver injury and suggest that quercetin may be useful in the preventing the development of hepatic fibrosis.

Heptic fibrosis/cirrhosis is a common hepatic disease characterized by the hyper-accumulation of connective tissue components, and hepatic necrosis. Chronic alcohol ingestion, viral infection, and metabolic disorders are contributing factors and there has been no effective treatment. Hepatocyte growth factor (HGF), originally identified as a potent mitogen for mature hepatocytes, is a long-sought hepatotrophic factor for liver regeneration. Administration of human recombinant HGF into rats with hepatic fibrosis/cirrhosis caused by dimethylnitrosamine (DMN) elicited mitogenic action for hepatocytes, stimulated hepatic collagenase activity, and prevented the onset and progression of hepatic fibrosis/cirrhosis. Accumulation of fibrous tissue components in the liver due to DMN-treatment were markedly decreased in HGF-injected rats. Moreover, HGF completely abrogated death caused by severe hepatic cirrhosis and dysfunction. We postulate that HGF may prove to be an effective treatment for human liver fibrosis/cirrhosis and for chronic hepatic failure.

In normal liver, fat-storing cells are the main storage site of vitamin A derivatives, mainly of retinyl palmitate and oleate. During liver injury, the phenotype of fat-storing cells alters dramatically. The cells gradually lose their fat-droplets, proliferate and synthesize large amounts of connective tissue molecules. In the present paper, we summarize the characteristics of fat-storing cells, review the role of fat-storing cells in development of hepatic fibrosis, and describe how retinoids affect the protein synthesis and proliferation of these cells.