Role Of Lethal Lipotoxic Hepatocyte Injury

Hepatocytes are involved in synthesizing proteins, cholesterol, bile salts, fibrinogen, phospholipids and glycoproteins. Additionally, hepatocytes ensure that our

Thus, there is an urgency to evaluate the effects of immune response on APAP toxicity using a human KCs and hepatocyte co-culture system. Since a 3D multicellular system containing hepatocytes and other non-hepatocytes can better reflect the cell-cell interactions of a real situation [11], in this study, we used the 3D liver microtissues consisting of primary human hepatocytes (PHH) and KCs (1 : 1) to study the inflammation-mediated hepatotoxicity after acetaminophen overdose.

Liver disease commonly known as Non Alchoholic Fatty Liver Disease (NAFLD) is esstmated to be present in as much as 86% of everyone who suffer from severe obesity. If left untreated, it has the potential to damage thee liver and lead to the development of cirrhosis

The ability of p53 to regulate metabolism is also associated with the ability to regulate cellular ROS levels. As previously mentioned, p53 can either remove damaged cells that have suffered sustained oxidative stress, or limit levels of ROS in order to lower oxidative stress and consequently, potential cell damage. Through the regulation of carbohydrate and lipid metabolism, p53 is able to influence the response to ROS accordingly. By driving the expression of TIGAR and promoting PPP activity, p53 can increase the production of NAPDH, which can be used to generate the cellular antioxidant GSH (Bensaad 2006). Moreover, at the expense of nucleotide synthesis, p53 can also promote GSH synthesis following serine starvation, thereby lowering ROS

Chronic liver diseases and liver biopsy. Chronic liver diseases encompass many different causes, including viral infections, nonalcoholic fatty liver disease (NAFLD), alcohol abuse, primary sclerosing cholangitis, primary hemochromatosis, and autoimmune disease. All of these precipitate chronic damage to the liver via necroinflammation and subsequent cellular injury and accumulation of extracellular matrix (ECM) proteins distorting the hepatic architecture by forming hepatic fibrosis with abnormal collagen deposition. Without treatment, the eventual development of cirrhosis (the end stage of fibrosis) can accelerate to hepatocellular dysfunction, hepatic insufficiency, portal hypertension, and hepatocellular carcinoma (HCC), thus

Our previous data suggests that extracellular vesicles (EVs) released from stressed steatotic hepatocytes are chemotactic toward macrophages (6), therefore, we next looked at circulating EVs in all four groups of mice. As predicted there was an increase in circulating EVs in mice fed the FFC diet in comparison to chow-fed mice (Fig. 7A). FFC-fed mice treated with FTY720 (treated group) had lower circulating EVs than the FFC-fed saline injected (control group) mice, though the circulating EVs in this group (FFC-FTY) remained higher than the chow-fed FTY treated group (Fig. 7A). This reduction in EVs is likely due to a reduction in liver injury in the FFC-fed FTY treated group, though we cannot exclude a direct effect of FTY720 on release of EVs by steatotic hepatocytes. Furthermore, though EVs were lower in the treated group (FFC-FTY), the EV S1P content and C16:0 ceramide content were not lower (Fig. 7B). This supports our hypothesis that EV S1P acts as a chemoattractant to macrophages via S1P receptor activation on macrophages; and that FTY720 administration to mice impairs the recruitment of proinflammatory monocyte-derived macrophages to the

During ischemia, the intracellular and extracellular adenosine and three phosphate (ATP) is depleted, leading to increased ATP degradation products, such as adenosine, hypoxanthine, xanthine and a shift towards anaerobic metabolism [3]. However, on reperfusion, the initial increase in oxygen delivery amount exceeds the amount needed for cellular metabolism from anaerobic pathways back to aerobic pathways. The whole process would lead to generation of damaging free radicals and a wide variety of reactive oxygen species (ROS) are generated, including superoxide radical, hydrogen peroxide and hydroxyl radical. Even though hepatocyte can directly produce ROS, physiologically Kupffer cells are thought to be the main source of ROS in the early stages of live ischemia-reperfusion injury followed by natural killer T-cells generating ROS and neutrophils being the main source in the very later stages [4, 5].

The progression from fibrosis to cirrhosis, the end-point of CLDs, is distinguished by a prolonged inflammatory and fibrogenic process that leads to an abnormal angioarchitecture distinctive for cirrhosis. Several mechanisms are responsible for the angiogenic switch during the pathogenesis of CLDs. First, CLDs are characterised by chronic inflammation. Increased intrahepatic vascular resistance is primarily caused by anatomical changes, such as fibrotic scar tissue compressing portal and central venules. In addition, the formation of fibrotic septa, as well as sinusoidal capillarisation, can result in an increased resistance to blood flow and oxygen delivery. This results in hypoxia and the transcription of hypoxia-sensitive pro-angiogenic

Dr. Kosmider has publications with Dr. Steven Kelsen, who is a co-investigator on this grant. His clinical and research interests are focused on signaling pathways and the pathophysiology of oxidant stress-induced epithelial injury. He has training in respiratory medicine and physiology and will provide knowledge of the lung diseases. He has also collaborated with Dr. Muniswamy Madesh, a co-investigator in this project, who is an expert in studies of mitochondrial dysfunction and mechanisms of mitochondrial induced apoptosis.

Microarray analysis displays activated the expression of genes related in apoptosis pathways and suppressed the expression of genes involved in cell cycle and DNA replication and repair process after idiosyncratic drug exposure. Meanwhile, the specific immune reaction induced-TNF secretion disrupts the balance of the metabolism of sphingolipids and boosts the concentration of ceramides. The increase in ceramides, especially the long-chain and very long-chain ceramides, alters mitochondrial membrane permeability. Taken together, the inflammatory

Usual liver function demands hepatocellular basal autophagy. Due to their high biosynthetic project and character in protein turnover and carbohydrate depositary, hepatocytes may be especially dependent on basal autophagy for their normal physiological tasks. Autophagy appears to play a major function not only in common liver physiology, but also in the pathogenesis of liver problems such as nonalcoholic and alcoholic fatty liver, drug- affected liver damage, protein conformational liver disorder, viral hepatitis, liver cancer, and liver ischemia-reperfusion

The major harmful effects of free radicals include oxidative stress and nitrosative death. Oxidative death is caused by ROS and nitrosative death by RNS. When the cells are unable to maintain the state of ‘Redox Homeostasis’ (keeping equilibrium between the beneficial and harmful effects of free radicals) it causes oxidative stress through the generation of ROS (12) and resultant oxidative injury. Potential biological damage happens when there is an overproduction of ROS and RNS and a down regulation of enzymatic and non-enzymatic antioxidants. Since ROS owns impact of powerful oxidizing agents, they interfere with the expression of a number of genes involved in the activation of signal transduction cascades (13, 14), apoptosis (15,16) etc.

Figure 2. Liver histology. Photomicrographs of lipid droplets stained with Oil Red O. Liver morphology of control groups at 3, 4 and 5 months (A, C and E, respectively) with few lipid droplets present, indicated by the arrows. Liver morphology of groups exposure to CdCl2 at 3, 4 and 5 months (B, D and F respectively), lipid droplets indicated by the arrows. Cadmium groups showed both macrovesicular (ballooning of hepatocytes, white dotted circles) and microvesicular injurie (foaming in hepatocytes, blue dotted circles); lesions are characteristic of hepatic steatosis. Scale bars, 50µm.

Tumor necrosis factor alpha (TNFα) and Interleukin-6 (IL-6) are identified to cause NAFLD. But, (TNFα) is linked to cause insulin resistance and progression to NASH. Treatment with anti-TNFα therapy shows improvement in NAFLD.

A number of pathologic conditions lead to acute ER stress and activate the UPR – for example, nutrient deprivation, disruption of calcium homeostasis, viral infection, and secretory protein mutations. Depending on the severity of ER stress, the UPR can result in cell death through the activation of apoptotic pathways mediated specifically by the ER and the mitochondrial pathways (Ma and Hendershot, 2004). The glucose-regulated protein GRP78, also referred to as BiP (immunoglobulin heavy-chain binding protein), which is a major component of adaptive survival response, resides primarily in the ER. It belongs to the HSP70 protein family, which plays critical roles in the stress of oncogenesis.