الفهرس 
Abstract and aim of the workOnly 14 pages are availabe for public view
 |  | from | 199 |  |  |
| | | from | 199 | | |
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) Is Deposition Of Fat In The Liver Of A Non-Alcoholic Subject, A Condition Which May Progress To End-Stage Liver Disease. It Is A Common Clinicopathological Condition characterized By Significant Lipid Deposition In The Hepatocytes Of The Liver Parenchyma. NAFLD Comprises A Wide Spectrum Of Liver Damage, Ranging from Simple Macrovesicular Steatosis To Steatohepatitis, Advanced Fibrosis, And Cirrhosis.
NAFLD Is The Most Common Cause Of chronic Liver Disease In The Developed World .NAFLD Refers To A Spectrum Of Liver Disorders Occurring Due To Abnormal Fat Deposition In The Liver, Which Ranges In Severity from Simple Hepatic Steatosis With No Inflammation, To Steatohepatitis (NASH) Which Can Progress To Liver Cirrhosis. Excess Energy Intake And Obesity, In Combination With Different Genetic And Environmental Factors, Can Lead To The Development Of Insulin Resistance. A Combination Of Insulin Resistance, Along With Excess Accumulation Of Free Fatty Acids And Increased Intracellular Formation Of Toxic Lipid Metabolites (Such As Products Of Lipid Peroxidation), Is Thought To Elicit An Inflammatory Response That Triggers The Progression To NAFLD One Of The Major Risks For Developing NAFLD Is High Fat Diet In Both Rats And Human.
Excess Energy Intake And Obesity, In Combination With Different Genetic And Environmental Factors, Can Lead To The Development Of Insulin Resistance. A Combination Of Insulin Resistance, Along With Excess Accumulation Of Free Fatty Acids And Increased Intracellular Formation Of Toxic Lipid Metabolites (Such As Products Of Lipid Peroxidation), Is Thought To Elicit An Inflammatory Response That Triggers The Progression To NAFLD.
A Variety Of Conditions Such As Excess Delivery Of Fatty Acids, Decreased Oxidation Of Hepatic Fatty Acid And/Or Impaired Synthesis Or Secretion Of Very Low-Density Lipoprotein Increase The Sources Of Hepatic Lipids, Leading To Fatty Liver Disease. The Amount Of Accumulated Fat Is Also Increased By Lipogenesis; Emerging Evidence Supports The Importance Of De Novo Lipogenesis In Abnormal Hepatic Fat Accumulation In NAFLD Patients. Lipogenesis Is Transcriptionally Regulated By The Membrane-Bound Sterol Regulatory Element, Binding Protein-1c (SREBP-1c). Liver X Receptor-Α (Lxrα), A Transcriptional Nuclear Receptor, Is A Key Regulator Of Lipogenic Genes Encoding For The Enzymes That Promote Hepatic Fat Accumulation (E.G. Fatty Acid Synthase, FAS; Acetyl-Coa Carboxylase, ACC; And Stearoyl-Coa Desaturase-1, SCD-1) . Ligand Activation Of Lxrα Promotes Induction Of The Lipogenic Genes Through SREBP-1c, Causing Increases In Fatty Acid Synthesis And Progression To Steatosis, Hypertriglyceridemia, And Steatohepatitis .Thus, SREBP-1c Is An Important Target Gene Of Lxrα. Since The Lxrα- SREBP-1c Pathway Activates Lipogenesis In The Liver, It Is An Attractive Target For The Treatment Of Hepatic Steatosis And Hepatitis.
In Addition To Lxrα, Recent Studies Have Suggested That Forkhead-O1 Transcription Factor (FOXO1), A Member Of The Forkhead ‘Other’ group Of Transcription Factors And An Important Target Of Insulin And Growth Factor Signaling , Also May Contribute To The Regulation Of SREBP1c. Recent Data Indicate That Forkhead Box O1 (Foxo1), A Nuclear Transcription Factor Known To Be A Mediator Of Insulin Signaling, Plays An Important Role In Hepatic Regulation Of Apolipoprotein C-III (Apoc-III), An Important Player In Plasma VLDL-TG Metabolism.
Fibroblast Growth Factor-19 (FGF-19) Was Originally Identified As A Signal Promoting The Development Of The Inner Ear In Chick Embryos. FGF-19 Increased The Activity Of STAT3, An Inhibitor Of SREBP-1c Expression And Decreased The Expression Of Peroxisome Proliferator-Activated Receptor-Γ Coactivator-1β (PGC-1β), An Activator Of SREBP-1c Activity. FGF-19 Also Increased The Expression Of Small Heterodimer Partner (SHP), A Transcriptional Repressor That Inhibits Lipogenic Enzyme Expression Via A SREBP-1c-Independent Mechanism. Inhibition Of SREBP-1c Activity By Changes In STAT3 And PGC-1β Activity And Inhibition Of Gene Transcription By An Elevation In SHP Expression Can Explain The Inhibition Of Lipogenesis Caused By FGF-19 .
Recent Evidence Suggests That Supraphysiological Concentrations Of Ffas Induce Fibroblast Growth Factor-21(FGF-21) Secretion (I.E., Starvation And Intense Physical Activity) Through The Peroxisome Proliferator-Activated Receptor Alpha (Pparα) Pathway .The Rise In FGF21 Levels Is Aimed At Improving Energy Production (Ketogenesis) And Utilization (Oxidation) Of Ffas. FGF21 Increment May Protect Against chronic Exposure To High Concentrations Of Ffas, Which Causes Lipotoxicity In Muscle, Pancreas, And Liver .
Peroxisome Proliferator-Activated Receptor Alpha. Pparα Is A Transcription Factor Known To Reduce Plasma Lipids And Increase Mitochondrial Beta Oxidation.
Omega-3 Fatty Acids Are Key Regulators Of Hepatic Gene Transcription, With Peroxisome Proliferator-Activated Receptor Alpha (Ppara) And Sterol Regulatory Element Binding Protein-1c (SREBP-1c) Being Best Known .
Recently, It Has Been Recorded That Ginger Prevents Obesity In Mice Fed A High-Fat Diet, It Inhibits The Hydroxymethylglutaryl Co A (HMG-Co A) Reductase Which Is A Rate Limiting Enzyme For Cholesterol Biosynthesis (Like That Of Statins). It Also Promotes Excretion And Impairs Absorption Of Cholesterol (It Increases The Activity Of 7- Alphahydroxylase, The Rate Limiting Enzyme In The Catabolic Conversion Of Cholesterol To Bile Acids In Liver .It Also Reduces The Extent Of Lipogenesis By Downregulating SREBP-1c And Its Related Molecules, Which Leads To The Enhancement Of Fatty Acid Β-Oxidation And The Suppression Of Body Fat Accumulation .
Ginger (Zingiber Officinale Roscoe , Zingibereaceae), A Rhizomatous Perennial Plant,Has Been Used Around The World As A Spice In Food And Beverages. Ginger Extract Contains Pungent Phenolic Compound , Such As 6-Gingerol And 6- Shogoal, That Have Been Demonstrated To Have Anti- Inflammatory And Antioxidant For Treatment Of NAFLD. Supplementation With [6]-Gingerol Analogue, A Major Chemical Component Of The Ginger Rhizome To Mice Fed A High-Fat Diet Significantly Reduced Fat Accumulation. Moreover, Ginger May Improve Lipid Metabolism In Hyperlipidemic Cholesterol Enriched-Diet Rats .
An Omega-3 Fatty Acid Such As DHA And EPA Which Mainly Found In Deep Sea Fish. Polyunsaturated Fatty Acids (Pufas), Especially N-3 Pufas, Are Used To Promote Weight Loss, And To Reduce Hepatic Triglyceride Accumulation, While Improving Insulin Sensitivity And Reducing Steatosis, And Hepatic Damage In Patients With NAFLD. DHA And EPA Have Been Shown To Activate The Peroxisome Proliferator Activated Receptor (PPAR)-Α And Inhibit The Sterol Regulatory Element Binding Protein (SREBP). Increasing The Activity Of PPAR-Α Has Been Shown To Prevent And Even Reverse Experimental NASH. Additionally, A 7 Days Animal Study Indicated DHA And EPA Are Capable Of Inhibiting Hepatic SREBP-1c Resulting In The Downregulation Of Genes Involved In Fatty Acid Synthesis (E.G. Fatty Acid Synthase And Acetyl Coa Carboxylase) .
The Potential Anti-Infammatory Effects Of EPA And DHA May Prevent The Progression Of Simple Steatosis To Steatohepatitis (NASH) Thus Preventing The Development Of NAFLD. Omega-3 Fatty Acids Increase Expression, Phosphorylation And Activity Of The Major Isoform Α 1 AMPK In Macrophages. Besides That , Omega-3 Fatty Acids Cause Inactivation Of NF-Κb Signaling Via Keeping IKB(The Inhibitory Subunit Of NF-Κb Complex) Bound To NF-Κb Leading To Suppression Of Pro-Inflammatory Gene Expression.
Our Interest Has Been Centered On The Changes Observed In Activities And Levels Of These Parameters In NAFLD Model. Also, To Determine The Effect Of These Parameters In Modulation Of Lipogenesis And Metabolic Disturbances With It.
Sixty Male Wister Albino Rats Were Used In This Study They Were Divided Into Six Groups ; Each Was Comprised Of Ten Rats.
group I (Normal Control): Rats Were Fed On A Normal Chow Diet For 20 Weeks And Administered Water As A Vehicle Via Oral Gavage.
group II (High Fat Diet Group): Rats Were Fed On The High Fat Diet For 20 Weeks And Administered Water As A Vehicle Via Oral Gavage.
group III (Ginger Treated Group): Rats Were Fed On A Normal Chow Diet For 20 Weeks And Administered Ginger Daily For The Last Two Consecutive Weeks Via Oral Gavage In A Dose Accounting For (200 Mg/ Kg Body Weight) Of Giger Extract.
group IV (Omega-3-Fatty Acid Treated Group): Rats Were Fed On A Normal Chow Diet For 20 Weeks And Administered Fish Oil Daily For The Last Two Consecutive Weeks Via Oral Gavage In A Dose Accounting For (0.8 Gm/ Kg Body Weight) Of Omega-3fatty Acid.
group V (High Fat Diet Ginger Treated Group): Rats Were Fed On The High Fat Diet For 20 Weeks And Administered Ginger Daily For The Last Two Consecutive Weeks Via Oral Gavage In A Dose Accounting For (200 Mg/ Kg Body Weight) Of Ginger Extract.
group VI (High Fat Diet Omega-3-Fatty Acid Treated Group): Rats Were Fed On The High Fat Diet For 20 Weeks And Administered Fish Oil Daily For The Last Two Consecutive Weeks Via Oral Gavage In A Dose Accounting For (0.8 Gm/ Kg Body Weight) Of Omega-3fatty Acid.
The Final Body Weight Of Rats Was Recorded, Then The Rats Were Sacrificed At The End Of The Experiment After About 18 Hours Fasting To Minimize Variation In Lipid Pattern During Two Successive Days. Blood Samples Were Collected from Retro-Orbital Vein Into Tubes Containing EDTA And Centrifuged At 1500 Rpm For 30 Minutes. An Aliquot Of The Separated Plasma Was Used For Immediate Estimation Of Fasting Blood Glucose. Second Aliquot Was Kept On -20ºc For Further Analysis. Liver Was Separated Immediately After Blood Samples Collection. The Livers Were Excised Immediately, Then Washed With 0.9% Physiological Saline And Dried from The Excess Saline Using Dry Filter Paper. The Part Was Cut from Livers Were Divided Into Three Parts, The First Part Placed In Proteinase Inhibitor And Preserved At -80ºc For Western Blot Studies.A Second Part Of Liver Was Placed In Rnase Inhibitor And Preserved At -80ºc For RT-PCR.Third Part Of The Liver Was Preserved In 10% Formalin Solution For Histopathological Examination.
The Results Revealed That:
In High Fat Diet Group, The Level Of SREBP-1C, LXR-Α, FOXO1, PGC1 Β Were Significantly Elevated Compared To Those Of Normal Control. In Addition HFD Showed A Significant Decrease In FGF-19 And STAT3 Compared To Those Of Normal Control Group. Also, HFD Treated group Showed A Significant Increase In The Level Of Plasma Glucose , Triglycerides (TAG), Non-Estrified Fatty Acid And Total Cholesterol With A Little Effect On HDL-C Compared To Those Of Normal Control Group. Furthermore, HFD Induced Significant Elevation In Final Body Weight Compared To Those Of Normal Treated Group.
In Contrast Administration Of Either Ginger Extract Or Omega-3 Fatty Acid To HFD Treated Rats Showed Significant Reduction In The Level Of SREBP-1C, LXR-Α, FOXO1, PGC1 Β. Additionally, The Level Of FGF-19 And STAT3 Were Elevated In Groups Treated With Ginger And Omega-3 Fatty Acid Compared To Those Of HFD Treated Group. Also, Ginger And Omega-3 Fatty Acid Treated group Showed A Significant Decrease In The Level Of Plasma Glucose , Triglycerides (TAG), Non-Estrified Fatty Acid And Total Cholesterol With A Little Effect On HDL-C Compared To Those Of HFD Treated Group. Furthermore, Ginger And Omega-3 Fatty Acid Induced A Significant Decrease In Final Body Weight Compared To HFD Treated Group.
6.2. Conclusion
Either Ginger Extract Or Omega-3 Fatty Acid Was Thought To Exert Their Beneficial Effect Via Modulation Of Lipogenesis And Metabolic Abnormalities Associated With NAFLD Induced By HFD. Their Effects Were Induced Via Downregulation Of SREBP-1C, LXR-Α, FOXO1, PGC1 Β. As Well As Up Regulation Of FGF-19 And STAT3.
Data Obtained from Ginger Elucidated That It Was More Effective Than Omega-3 Fatty Acid And It Had A Better Modulation Of Lipogenesis In Non Alcoholic Fatty Liver Disease.