الفهرس 
Title pageOnly 14 pages are availabe for public view
 |  | from | 139 |  |  |
| | | from | 139 | | |
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered the commonest cause of liver disease in humans. The main characteristic of NAFLD is excessive TG accumulation in the hepatocytes. NAFLD ranges from simple steatosis to NASH and can eventually result in cirrhosis, liver failure, and/or HCC. The pathogenesis of NAFLD has been explained by the two hit model for long time, that involve hepatic TG accumulation as the first hit while hepatocyte injury as well as, mitochondrial dysfunction and/or ER stress represent the second hit. The two hit theory is now being modified by the multiple parallel hits model. This model suggests that hepatic steatosis may represent an epiphenomenon of several distinct injurious mechanisms including IR instead of being a true “first hit”.
Sirtuin 1 (SIRT1) is a NAD+-dependent protein deacetylase that regulates the metabolic response to calorie restriction and fasting in mammals. During times of nutrient deficiency, SIRT1-catalyzed deacetylation of PGC-1α induces hepatic gluconeogenesis and FA oxidation, moreover, SIRT1 promotes metabolic efficiency through elevation of adiponectin in adipose tissue. SIRT1 can also suppress inflammation. SIRT1 has the potential to improve NAFLD through regulation of both lipid and carbohydrate metabolism as well as, through its anti-inflammatory and anti-oxidant roles.
PPARα is nuclear receptor that is crucial in the regulation of lipid transport and metabolism mainly through the activation of mitochondrial and peroxisomal FA β-oxidation pathways. PPARα induces the transcription of genes encoding FA-metabolizing enzymes and mitochondrial FA oxidase activity, primarily in the liver. PPARα downregulates inflammatory genes induced by NF-κB and decreases expression of CRP induced by IL-1 in human hepatocytes.
Peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α is a transcription coactivator that interacts with many transcription factors that contribute in a several biological responses such as, adaptive thermogenesis, mitochondrial biogenesis (Mitogenesis), glucose/FA metabolism.
Curcumin is a naturally occurring polyphenol derived from turmeric. It has been a subject for extensive research over recent decades due to its potential to interacte with hundreds of molecular targets and several pharmacological benefits. Curcumin has been found to possess antioxidant, anti-inflammatory, anticancer, antiarthritic, antidepressant, anti-diabetic, and lipid-lowering effects in clinical practice. The potential of curcumin to improve insulin sensitivity, reduce lipogenesis, and ameliorate inflammation and oxidative stress could be used for the prevention of steatosis and its transition into steatohepatitis.
The present study aimed at investigating the effect of curcumin on gene expression of hepatic SIRT1in experimental NALFD.
The study was conducted on 60 male wister rats, the rats were divided into four groups, each group contained fifteen rats. group І (Control group) received standard rat chew diet. group ІI (Untreated group) comprised of rats that received HFD. At eighth week fatty liver disease was confirmed by histolopathological examination of the liver through scarification of number rats. group III (DMSO-treated group) in which FL was induced as previously performed in group II and then was injected intraperitoneally day after a day with 1 ml/kg body weight dimethyl sulfoxide (DMSO) for 4 weeks. group ІV (Curcumin-treated group) in which FLwas induced as previously performed in group II and then was injected intraperitoneally day after a day with 100 mg/kg of curcumin dissolved in DMSO for 4 weeks.
The current study results revealed increased hepatic cholesterol and TG contents in the untreated group in comparison to their contents in control group and this was reversed by curcumin treatment. The current study results also showed upregulated gene expression of SIRT1, PPARα and PGC-1α as well as increased hepatic content of SIRT1 in untreated group compared to control group. On the other hand, curcumin treatment downregulated the gene expression of PGC-1α and reduced the hepatic SIRT1 content compared to untreated group. Moreover, curcumin treatment has returned level of hepatic SIRT1 gene expression similar to control group. On the contrary, levels of hepatic gene expression of PPARα werenot significantly influenced by curcumin treatment, higher doses of curcumin and longer durations of treatment are recommended in the future studies.
from the findings of this study it can be concluded that:
The hepatic cell responds to steatosis by upregulation of expression of genes that reduces the effect of steatosis (Compensative response).
In the current study, the compensative response was represented by upregulation of hepatic gene expression of SIRT1, PPARα and PGC-1α.
Curcumin treatment resulted in downregulation of hepatic gene expression of PGC-1α and reduction of hepatic SIRT1 content combared to their levels in untreated group, moreover, curcumin treatment reduced SIRT1 gene expression to a level similar to control group. This reduction in compensative response elicited towards steatosis may add to the beneficial effect of curcumin in reducing steatosis.
On the contrary, levels of hepatic gene expression of PPARα were not significantly influenced by curcumin treatment. Higher doses and longer durations of the treatment are recommended in the future studies.
from the finding of this study it can be recommended that:
Extra studies are needed for understanding the pathogenesis of NAFLD.
Curcumin is recommended as a possible treatment for NAFLD due to its lipid lowering effect as well as its anti-inflammatory effect.
Extra studies on the human subjects are recommended to confirm the beneficial role of curcumin in treatment of NAFLD.
Higher doses of curcumin and longer durations of treatment are recommended in the future studies.