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Finelli, C. Mediators of Hepatotoxicity from Excess of Lipids. Encyclopedia. Available online: https://encyclopedia.pub/entry/45603 (accessed on 25 June 2024).
Finelli C. Mediators of Hepatotoxicity from Excess of Lipids. Encyclopedia. Available at: https://encyclopedia.pub/entry/45603. Accessed June 25, 2024.
Finelli, Carmine. "Mediators of Hepatotoxicity from Excess of Lipids" Encyclopedia, https://encyclopedia.pub/entry/45603 (accessed June 25, 2024).
Finelli, C. (2023, June 15). Mediators of Hepatotoxicity from Excess of Lipids. In Encyclopedia. https://encyclopedia.pub/entry/45603
Finelli, Carmine. "Mediators of Hepatotoxicity from Excess of Lipids." Encyclopedia. Web. 15 June, 2023.
Mediators of Hepatotoxicity from Excess of Lipids
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Non-alcoholic fatty liver disease (NAFLD) is currently the leading cause of chronic liver disease in Western countries; the molecular mechanisms leading to NAFLD are only partially understood and there are no effective therapeutic interventions. The prevalence of liver disease is constantly increasing in industrialized countries due to a number of lifestyle variables, including excessive caloric intake, unbalanced diet, lack of physical activity, and abuse of hepatotoxic medicines. 

mediators of hepatotoxicity lipids hepatic statosis toll-like receptors

1. Introduction

It has been shown that hepatic steatosis, formerly thought to be the start of non-alcoholic fatty liver disease (NAFLD), is actually a healthy increase in triglycerides, whereas free fatty acids are the toxic molecules that lead to steatohepatitis and fibrosis [1][2]. In a mouse model, genetic suppression of the enzyme diacylglycerol acyltransferase 2 (DGAT2) decreased hepatic steatosis while increasing fibrosis due to the toxic effects of FFAs [3]. Lipotoxicity mediated by FFAs (cellular toxicity caused by fat accumulation) in liver cells may originate from the disruption of triglyceride synthesis [4].
NAFLD is a group of diseases that include cirrhosis, steatosis, and steatohepatitis, which are characterized by fatty infiltration of the liver. NAFLD is the most common liver disease, with an estimated prevalence worldwide of around 25% [5]. The current epidemic of obesity and metabolic syndrome, which manifest in the liver as NAFLD, may be responsible for the sudden increase in the incidence of NAFLD [6]. The majority of patients with NAFLD have simple hepatic steatosis without steatohepatitis and fibrosis. In addition, in 2–3% of individuals, NAFLD can become non-alcoholic steatohepatitis (NASH), which can lead to progressive fibrosis, cirrhosis, and consequences such as hepatocellular carcinoma [7][8][9]. As much as 50% of patients with simple steatosis who later develop NASH may also develop severe fibrosis [10].
The parenchyma of the liver is made up of a variety of cell types, the bulk of which are hepatocytes (around 70% of the liver cell population) [11]. Parenchymal cells include hepatocytes and cholangiocytes, while nonparenchymal cells consist of Kupffer cells, stellate cells, and endothelial cells. Hepatic cells orchestrate the development of liver disorders. Hepatocytes, macrophages, and hepatic stellate cells interact in NAFLD and its severe variant, non-alcoholic steatohepatitis (NASH), although the precise methods through which these cells are orchestrated are not fully understood [11][12].
Patients with NAFLD have higher levels of oleic acid, a monounsaturated fatty acid (MUFA), and palmitic acid, according to studies examining the makeup of hepatic and circulatory free fatty acids (a saturated fatty acid (SFA)) [13][14]. However, polyunsaturated fatty acids have not been demonstrated to be toxic to hepatocytes and may even be beneficial in NAFLD patients [15][16]. Experimental research on this subject in human B cells has examined the function of stearoyl-CoA desaturase-1 (SCD1), the enzyme that changes SFA into MUFA [17]. More MUFAs are produced because of the increased expression of SCD1, and these MUFAs are then incorporated into triglycerides to produce simple and well-tolerated hepatic steatosis [18]. However, the removal of SCD1 results in the accumulation of SFA, which in turn triggers hepatocyte death and steatohepatitis [19]. Therefore, the type of FFAs stored in hepatocytes is just as important for developing NAFLD as the amount of FFAs accumulated, if not more [20]. Apoptosis, a form of programmed cellular death, is considered a key mechanism in developing NAFLD [21][22]. The main pathogenic mechanism seen in the biopsy samples of NASH patients is apoptosis, and in the spectrum of NAFLD, the presence of apoptosis helps to identify NASH patients from those with simple steatosis [23]. Patients who have higher levels of apoptosis will have advanced fibrosis because the degree of apoptosis and inflammation are inversely correlated [24]. The correlation between the levels of circulating cytokeratin-18 fragments, which are indicators of apoptotic liver cells, and the degree of fibrosis, provides additional evidence that apoptosis plays a significant role in NASH [25]. Lipoapoptosis is the name given to apoptosis mediated by FFAs [26]. Activation of the apoptotic pathways may occur either by an extrinsic pathway mediated by cell surface receptors or by an intrinsically mediated pathway by intracellular organelles [27].
A fundamental component of NASH is the lipotoxicity of hepatocytes. Lipotoxicity is caused by the accumulation of lipid intermediates, which cause cell malfunction and cell death. In NASH, hepatocytes build up triglycerides and various lipid metabolites, including free cholesterol, ceramides, and free fatty acids (FFA) [28]. Hepatocytes store most fatty acids as triglycerides, and some data suggest that the esterification of fatty acids into neutral triglycerides provides a protection mechanism against lipotoxicity [4][29]. On the other hand, FFA causes liver damage and activates specific signaling stunts, resulting in hepatocytic apoptosis, which in this context is called lipoapoptosis [30]. FFA is thus regarded as a major mediator of the lipotoxicity of hepatocytes. In fact, in NASH, there is an increased hepatic inflow of FFA following increased lipolysis in the peripheral fat tissue due to insulin resistance [31]. The lipotoxicity of FFA in hepatocytes is partially mediated through their intracellular lysophosphatidyl choline metabolite, which has also been seen to increase in the liver of patients with NAFLD in proportion with the severity of the disease [29].
Antihyperlipidemic drugs frequently cause mixed hepatocellular or liver lesions, with rare cases of pure cholestatic image [32][33]. The cytochrome P450 system, bile acid transport protein dysfunction, immune-mediated inflammatory response to the drug or its metabolites, immune-mediated apoptosis by tumor necrosis factor, and oxidative stress as a result of intracellular damage are some of the various proposed mechanisms of hepatotoxicity that vary depending on the drug or drug class [34].

2. Mediators of Hepatotoxicity from Excess of Lipids

2.1. Toll-like Receptors

Toll-like receptors (TLRs) are pattern recognition receptors that are able to detect molecular forms associated with pathogens, and, as a result, they can activate the immune system by means of pro-inflammatory signaling pathways [35]. The production of adipocytokines such as TNF-α and IL-6 is high when TLR4-mediated upregulation of NF-κB is activated by saturated fatty acids such as palmitic acid [36]. A reduction in the expression of TLR4 in mutating mice has been shown to be protective against the development of NASH [37]. Mice that received high-fat diet and dextran sulfate sodium (DSS) had high levels of bacterial lipopolysaccharides in the portal circulation, a higher expression of TLR4, and severe liver inflammation when compared with the controls [38]. TLR4 may be the key component of the gut microbiota−liver axis, which influences the development of NASH [39]. In fact, TLR4 stimulation can stimulate the production of ROS by hepatic macrophages and improve the expression of pro-interleukin-1, eventually promoting the development of NASH [40]. This demonstrates how the etiology of NASH is affected by the impact of gut microbiota dysbiosis-mediated LPS/TLR4 activation.

2.2. Death Receptors

Death receptors, which are receptor family tumor necrosis factors on the cellular surface, are essential in extrinsic apoptotic pathways [41]. The liver expresses several death receptors and their ligands, including tumor necrosis factor receptor 1 (TNF-R1), TNF related apoptosis-inducing ligand receptor 1 and 2 (TRAILR1 and TRAIL-R2), Fas ligand (FasL), TNF-α, and TRAIL [42]. The death ligands in the extrinsic pathway bind their receptors to create a death complex, which then activates caspase-8 to cause apoptosis (caspases are proteolytic enzymes causing death) [43]. An essential characteristic of NASH is the over-expression of these death receptors and the resulting apoptosis [44].

2.3. Mitochondrial Dysfunction and Reactive Oxygen Species

Cell damage due to reactive oxygen species (ROS), a class of free radicals generated from molecular oxygen, is called “oxidative stress” [45]. Although the mitochondria are a major source of ROS and are generated by oxidative reactions within cells, levels of ROS are very low in healthy cells due to a variety of antioxidant defensive mechanisms [46][47]. The liver prefers to eliminate FFAs through mitochondrial β-oxidation in healthy individuals [48]. However, in NAFLD, there is an excess of FFAs, and the increase in mitochondrial β-oxidation translates into an increase in electron supply at the electron transport chain; this causes the electron transport chain to be over reduced and ROS to develop [49]. Given that mitochondrial DNA is likely to be damaged by ROS, a higher production of ROS results in mitochondrial malfunction, increasing the risk of ROS formation [50]. The release of proapoptotic proteins such as cytochrome c into the cytosol is produced by mitochondrial dysfunction caused by intracellular stress caused by an accumulation of ROS [51]. Apoptosome is an active complex formed when cytochrome c, apoptotic-protein activation factor-1 (Apaf-1), and caspase 9 attach [52]. Caspases 3, 6, and 7 downstream are activated by apoptosome to achieve the remaining stages of apoptosis [53].

2.4. Lysosomal Permeabilization

The investigation of molecular mechanisms makes it possible to discover the lysosomal−mitochondrial axis in FFA-induced lipotoxicity and the potential role of lysosomic permeability in the progression of NASH [54]. Mitochondrial dysfunction is considered to be the principal pathophysiologic process contributing to the progression of NALFD into NASH [55]. In human liver cells, lysosomal permeabilization and the release of the lysosomal protease cathepsin B occurred far earlier than mitochondrial dysfunction and cytochrome c release into the cytosol [56]. In addition, the inhibition of cathepsine B protects against lipotoxicity caused by FFA [4]. By activating hepatic stellate cells and promoting their development in the myofibroblasts of mice, cathepsin B is also related to the evolution of hepatic fibrosis [57].

2.5. Endoplasmic Reticulum Stress

An intracellular organelle called the endoplasmic reticulum (ER) carries out many critical tasks such as protein and lipid production [58]. When the ER is stressed (ER stress), it responds with a process known as an unfolded protein response (UPR) [59]. UPR aims to protect ER from stress caused by a number of factors, including viral infections, alcohol, and FFAs [60]. However, if stress in the ER goes on for a long time, UPR might be unable to handle it, causing apoptosis [61]. In vitro research, using different models of exocrine pancreas cells, has shown how saturated fatty acid, such as palmitic acid, could produce ER stress and hepatic cell death, furthering our understanding of the role of ER stress [62]. Apoptosis can also to be caused by FFAs in other ways, including mitochondrial dysfunction caused by the activation of c-Jun N-terminal kinase (JNK), mitochondrial permeabilization caused by the pro-apoptotic protein BAX, free cholesterol-mediated ER stress, and ceramide-mediated apoptosis induced by death ligands such as TNF and FAS [63] (Figure 1).
Figure 1. Possible mechanisms through which FFAs can lead to apoptosis. Lysosomal permeabilization, ER stress, and mitochondrial malfunction are all associated with the activation of the mitochondrial route of apoptosis. FFA may also upregulate and increase the amount of death receptors in the plasma membrane, such as Fas and TRAIL receptor 5 (DR5). These harmful fatty acids may also stimulate TLR4 signaling, which will increase the production of a number of cytokines that promote inflammation. Moreover, other lipid forms including ceramide and free cholesterol (FC) may cause mitochondrial malfunction and trigger the apoptotic pathway in the mitochondria. Abbreviations: SFA: saturated fatty acids; FC: free cholesterol; CE: cholesteryl-ester; ER: endoplasmic reticulum.

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