الفهرس 
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Abstract
NAFLD is characterized by triglycerides deposition in hepatocytes causing their injury and leading to NASH, fibrosis and cirrhosis. MG is a tropical fruit that contains a lot of bioactive anti-oxidant, and anti-adipogenic compounds.
This study was performed to establish an animal model for NAFLD/NASH by the use of high fat diet and to investigate the ability of MG to ameliorate NAFLD/NASH and its role in modulating apoptosis and autophagy within the injured hepatocytes in experimental animal model.
A total number of 100 adult male mice were divided into two experiments:
Experiment l : 40 animals divided into two sub-groups ; group I , 15 animals fed with standard diet and group II, 25 animals fed with HFD.
Experiment ll : 60 animals were randomly divided into six groups; ten animals each:
group I (control group) were fed SD .
group ΙΙ, were fed SD concomitant with MG in a dose of 50 mg/kg/day orally by gastric gavage.
group III, were fed HFD (71% fat, 11% carbohydrates and 18% protein) for 16 weeks .
group IV were fed HFD concomitant with MG in a dose of 50 mg/kg/day orally by gastric gavage for 16 weeks .
group V were fed HFD for 16 weeks followed by MG in a dose of 50 mg/kg/day orally by gastric gavage for 2 weeks.
group VI were fed HFD for 16 weeks followed by standard diet (SD) for 2 weeks .
In the last day of the experiment, body weight was measured in all groups and the animals were sacrificed after being anesthetized by intra peritoneal injection of ketamine in a dose of 100mg/kg body weight .Blood samples from the heart were taken for lipid profile and liver enzyme assay .The livers were excised , weighed and processed for examination by both light and electron microscopy for histological and histochemical studies to detect possible protective and therapeutic effects of MG against HFD induced NAFLD/NASH.
The results revealed that:
1-Experiment I
There was a significant increase in the animal body weight , liver weight coefficient , liver enzymes and plasma free fatty acids FFA (TC , TGs and LDL) with significant decrease in the HDL in HFD groups compared to that of the corresponding control groups which was progressive with the increase of the duration of HFD ingestion .Histologically The examined liver sections of HFD group showed Congestion and dilatation in portal vein , cellular infiltrations, apoptotic changes in the form of highly acidophilic cytoplasm and pyknotic nuclei ,the nuclei were of different sizes some of them were enlarged, while others were shrunken .Most of hepatocytes appeared with rarified cytoplasm .Dilatation of the central vein was observed, necrotic changes as pale acidophilic vacuolated cytoplasm and ballooning degeneration were seen in pericentral hepatocytes .Blood sinusoids appeared congested and dilated which contained numerous large kupffer cells. Many hepatocytes showed both macrovesicular and microvesicular steatosis mainly in zone 3. Ballooning degeneration , Mallory-Denk bodies and glycogenated nuclei were observed in some hepatocytes.
2- Experiment II:
The same changes were observed in HFD group as in experiment I. In addition ; increased collagen fibers in the portal areas and in the perisinusoidal spaces, an apparent decrease in PAS reaction , apparent increase in the positive immunostaining reaction of cleaved caspase-3 , α-SMA , LC3 and p62 in most of the hepatocytes and increase in immune reactivity of Kupffer cells. Ultrathin sections showed that hepatocytes had apoptotic , degenerative changes , vacuoles of variable shapes and sizes, large numbers of peroxisomes, megamitochondria and lipofuscin pigment deposition in cytoplasm also observed. Kupffer cells were increased in size and number with multiple lysosomes and phagosomes, collagen deposited in space of Disse with widening of space of Disse and interrupted endothelial lining of sinusoids.
MG groups ( VI &V) showed reduced body weight gain, liver weight coefficient, plasma free fatty acids levels and liver enzymes. Most of the histopathological changes observed in NASH were ameliorated. Immunohistochemical results showed that MG increased autophagy process and suppressed hepatocyte apoptosis. There was significant decrease in CD68 positive macrophages and significant decrease in α-SMA expression.
Conclusions: MG exerts effects by regulating hepatic lipid homeostasis , inflammation, apoptosis, and autophagy. Therefore, it could be a new approach to a dietary based method that delay the onset and development of steatohepatitis, liver cirrhosis and HCC risk by the prevention and management of NAFLD/NASH.
Recommendations
We recommend that:
1-HFD is a good animal model for NAFLD/NASH.
2-The use of MG as a protective and therapeutic agent in NAFLD/NASH is recommended.
3- Further clinical trial studies to clarify the effect of MG on human beings for better assessment of its effects in NAFLD/NASH patients.