curcumin and Choline-Deficiency

The cause of progression to non-alcoholic fatty liver disease (NAFLD) is not fully understood. In the present study, we aimed to investigate how curcumin, a natural phytopolyphenol pigment, ameliorates NAFLD. Initially, we demonstrated that curcumin dramatically suppresses fat accumulation and hepatic injury induced in methionine and choline-deficient (MCD) diet mice. The severity of hepatic inflammation was alleviated by curcumin treatment. To identify the proteins involved in the pathogenesis of NAFLD, we also characterized the hepatic proteome in MCD diet mice. As a result of two-dimensional proteomic analysis, it was confirmed that thirteen proteins including antioxidant protein were differentially expressed in hepatic steatosis. However, the difference in expression was markedly improved by curcumin treatment. Interestingly, eight of the identified proteins are known to undergo

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cell Line; Choline Deficiency; Curcumin; Disease Models, Animal; Endoplasmic Reticulum Stress; Glycosylation; Hexosamines; Inflammation Mediators; Liver; Male; Methionine; Mice, Inbred C57BL; N-Acetylglucosaminyltransferases; NF-kappa B; Non-alcoholic Fatty Liver Disease; Signal Transduction; Sirtuin 1; Superoxide Dismutase-1

Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has become one of the most common causes of chronic liver disease over the last decade in developed countries. NAFLD includes a spectrum of pathological hepatic changes, such as steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Bisdemethoxycurcumin (BDMC) is polyphenolic compounds with a diarylheptanoid skeleton, curcumin close analogues, which is derived from the Curcumae Longae Rhizoma. While the rich bioavailability research of curcumin, BDMC is the poor studies. We investigated whether BDMC has the hepatoprotective effect and combinatory preventive effect with silymarin on methionine choline deficient (MCD)-diet-induced NAFLD in C57BL/6J mice. C57BL/6J mice were divided into five groups of normal (normal diet without any treatment), MCD diet (MCD diet only), MCD + silymarin (SIL) 100 mg/kg group, MCD + BDMC 100 mg/kg group, MCD + SIL 50 mg/kg + BDMC 50 mg/kg group. Body weight, liver weight, liver function tests, histological changes were assessed and quantitative real-time polymerase chain reaction and Western blot analyses were conducted after 4 weeks. Mice lost body weight on the MCD-diet, but BDMC did not lose less than the MCD-diet group. Liver weights decreased from BDMC, but they increased significantly in the MCD-diet groups. All liver function test values decreased from the MCD-diet, whereas those from the BDMC increased significantly. The MCD- diet induced severe hepatic fatty accumulation, but the fatty change was reduced in the BDMC. The BDMC showed an inhibitory effect on liver lipogenesis by reducing associated gene expression caused by the MCD-diet. In all experiments, the combinations of BDMC with SIL had a synergistic effect against MCD-diet models. In conclusion, our findings indicate that BDMC has a potential suppressive effect on NAFLD. Therefore, our data suggest that BDMC may act as a novel and potent therapeutic agent against NAFLD.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Cholesterol; Choline; Choline Deficiency; Curcuma; Curcumin; Diarylheptanoids; Drug Synergism; Food, Formulated; Lipogenesis; Liver; Liver Function Tests; Male; Methionine; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Organ Size; Protective Agents; Silymarin; Triglycerides

Nonalcoholic steatohepatitis is characterized by the association of steatosis with hepatic cell injury, lobular inflammation and fibrosis. Curcumin is known for its antioxidant, anti-inflammatory and antifibrotic properties. The aim of this study was to test whether the administration of curcumin limits fibrogenic evolution in a murine model of nonalcoholic steatohepatitis. Male C57BL/6 mice were divided into four groups and fed a diet deficient in methionine and choline (MCD) or the same diet supplemented with methionine and choline for as long as 10 weeks. Curcumin (25 microg per mouse) or its vehicle (DMSO) was administered intraperitoneally every other day. Fibrosis was assessed by Sirius red staining and histomorphometry. Intrahepatic gene expression was measured by quantitative PCR. Hepatic oxidative stress was evaluated by staining for 8-OH deoxyguanosine. Myofibroblastic hepatic stellate cells (HSCs) were isolated from normal human liver tissue. The increase in serum ALT caused by the MCD diet was significantly reduced by curcumin after 4 weeks. Administration of the MCD diet was associated with histological steatosis and necro-inflammation, and this latter was significantly reduced in mice receiving curcumin. Curcumin also inhibited the generation of hepatic oxidative stress. Fibrosis was evident after 8 or 10 weeks of MCD diet and was also significantly reduced by curcumin. Curcumin decreased the intrahepatic gene expression of monocyte chemoattractant protein-1, CD11b, procollagen type I and tissue inhibitor of metalloprotease (TIMP)-1, together with protein levels of alpha-smooth muscle-actin, a marker of fibrogenic cells. In addition, curcumin reduced the generation of reactive oxygen species in cultured HSCs and inhibited the secretion of TIMP-1 both in basal conditions and after the induction of oxidative stress. In conclusion, curcumin administration effectively limits the development and progression of fibrosis in mice with experimental steatohepatitis, and reduces TIMP-1 secretion and oxidative stress in cultured stellate cells.

Topics: Actins; Alanine Transaminase; Animals; CD11b Antigen; Cells, Cultured; Chemokine CCL2; Choline; Choline Deficiency; Collagen Type I; Curcumin; Diet; Enzyme Inhibitors; Fatty Liver; Hepatic Stellate Cells; Humans; Liver; Liver Cirrhosis; Male; Methionine; Mice; Mice, Inbred C57BL; Muscle, Smooth; Oxidative Stress; Reactive Oxygen Species; Tissue Inhibitor of Metalloproteinase-1

While oxidative stress is a feature of non-alcoholic steatohepatitis, the causal link between oxidative stress and inflammatory recruitment has yet to be demonstrated. We analysed the role of NF-kappaB redox-sensitive signalling pathway of inflammatory recruitment in experimental steatohepatitis.. Mice were fed the methionine and choline deficient (MCD) or the control diet, with or without curcumin, an NF-kappaB inhibitor, for up to 4 weeks. Histopathology, lipoperoxides, NF-kappaB/DNA binding and expression of NF-kappaB-regulated genes were assessed.. MCD-fed mice developed steatohepatitis accompanied by dramatic accumulation of hepatic lipoperoxides, activation of NF-kappaB and induction of pro-inflammatory ICAM-1, COX-2, MCP-1 and CINC mRNA. Curcumin significantly reduced MCD-induced inflammation but had no effect on steatosis or on the level of hepatic lipid peroxides. Curcumin prevented the MCD-induced activation of NF-kappaB and decreased downstream induction of ICAM-1, COX-2 and MCP-1. However, it failed to reduce activation of AP-1, MAPK pathways or CINC expression.. Curcumin alleviates the severity of hepatic inflammation in experimental steatohepatitis induced by the MCD diet, an effect likely to be mediated via inhibition of NF-kB activation and dependent pro-inflammatory genes. The NF-kappaB pathway is one among several possible signalling pathways by which inflammation is recruited in experimental steatohepatitis.

Topics: Animals; Chemokine CCL2; Choline Deficiency; Collagen Type I; Curcumin; Cyclooxygenase 2; Deficiency Diseases; Diet; Enzyme Inhibitors; Fatty Liver; Female; Hepatitis; Inflammation Mediators; Intercellular Adhesion Molecule-1; Methionine; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; NF-kappa B; Prostaglandin-Endoperoxide Synthases; RNA, Messenger; Severity of Illness Index; Transcription Factor AP-1