الفهرس 
AcknowledgmentOnly 14 pages are availabe for public view
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Abstract
Fibrosis is a highly conserved response to hepatic injury, occurring in virtually all types of diseases with hepatocellular death including viral hepatitis (HCV&HBV) and nonalcoholic fatty liver diseases (NAFLD).
Fibrogenesis is a multicellular response with hepatic stellate cells (HSCs)
constituting the main effectors—contributing to approximately 90% of extracellular matrix (ECM)-producing myofibroblasts (Mederacke et al., 2013) and inflammatory signaling pathways. Inflammation is one of the most characteristic features of chronic liver disease of viral, alcoholic, fatty, and autoimmune origins. Inflammation is typically present in all disease stages and associated with the development of fibrosis, cirrhosis, and hepatocellular carcinoma (Seki and Schwabe, 2015).
Inflammasomes are multi-protein complexes expressed in different hepatic cells, and are characterized by a nucleotide-binding oligomerization domain (NOD)-like receptors (NLR), the sensor component of the inflammasome system. Activation of most inflammasomes is thought to be a two-step process. The first step is driven by signaling generated by toll-like receptors (TLR) or interleukin-1 receptor (IL-1R), and leads to expression of inflammasome components such as NLRs, caspase-1, pro-interleukin-(IL)-1β, and pro-IL18. Signal two is provided by Molecules derived from microbial or viral pathogens, commonly known as pathogen-associated molecular patterns (PAMPs), or sterile stimuli released from damaged hepatic cells, known as damage-associated molecular patterns (DAMPs) -mediated signaling, resulting in the formation of the multi-protein NLR inflammasome which entails pro-caspase-1 activation and cleavage of pro-IL-1β and pro-IL18 into their mature forms. The secreted, active IL-1β may further activate IL-1β-receptor leading to amplification of inflammasome signaling (Kubes and Mehal, 2012).
The last decade has seen a huge progress in our knowledge of genetic variants associated with common diseases (Price et al., 2015). Data from genome-wide association studies (GWAS) clarified the role of many genes in different disease condition, which consequently enabled researchers to study and understand the pathophysiology of many diseases as a pre step for drug discovery for these diseases(Hardy and Singleton, 2009). GWAS made a breakthrough in our understanding of liver fibrosis pathophysiology through linking between genes and liver fibrosis risk factor diseases eg. HBV, HCV, and NASH(Ge et al., 2009, Suppiah et al., 2009, Tanaka et al., 2009, Romeo et al., 2008, Lampertico et al., 2013). Looking to the future, these discoveries are expected to lead to improved diagnostics, and the identification of novel therapeutic targets (Eslam and George, 2016).
A recent GWAS identified a novel single-nucleotide polymorphism(SNP; rs641738) in the membrane bound O-acyltransferasedomain containing 7 gene (MBOAT7), to be associated with alcoholic cirrhosis(Buch et al., 2015).Starting from this finding we decided to investigate the role of this SNP and clarify the function of this gene in other liver fibrosis risk factor diseases including viral hepatitis (HBV&HCV), and NAFLD.
Results
1- Results for genotyping showed that MBOAT7 risk variant is significantly associated with liver inflammation and fibrosis in CHC, CHB, and NAFLD but no effect on liver steatosis except NAFLD.
2- MBOAT7 risk variant is significantly associated with low hepatic mRNA expression of MBOAT7.
3- Advanced stages of hepatic inflammation (A2-A3) are significantly associated with low hepatic MBOAT7 expression while early stages (A0-A1) are significantly associated with higher hepatic MBOAT7 expression.
4- MBOAT7 is widely expressed in different human body tissues and highly expressed in different types of immune cells.
5- Nearly all TLRs agonists except TLR3 can significantly reduce MBOAT7 expression in PBMCs. The highest reduction is associated with TLR4 agonist (LPS)
6- TLR4 agonist can reduce MBOAT7 expression in MDM and this reduction is time dependent.
7- MBOAT7 variant can control MBOAT7 expression in TLRs stimulated and un-stimulated PBMCs.
8- MBOAT7 variant can control Cytokines release from PBMCs following TLR2, TLR4, TLR9 stimulation. Also MBOAT7 variant can control Cytokines release from MDM following TLR4 stimulation.
9- MBOAT7 knockdown in LX2 cell line is significantly associated with higher mRNA expression of inflammatory cytokines and TLR 4. No effect of MBOAT7 knockdown on fibrotic markers.
10- MBOAT7 knockdown in MDM is significantly associated with higher mRNA expression of inflammatory cytokines. Also MBOAT7 knockdown is significantly associated with higher level of inflammatory eicosanoids.
11- MBOAT7 knockdown resulted in inflammasome activation through increasing caspase-1 activity, up regulation of pro-IL1β, and mature IL1β.
12- MBOAT7 knockdown is significantly associated with higher mRNA expression of ER-stress including IRE1, XPB1s, BIP, and Erdj4. These results were confirmed on protein level by western blot.