Free Fatty Acids Induce JNK-dependent Hepatocyte Lipoapoptosis
ABSTRACT Elevated serum free fatty acids (FFAs) and hepatocyte lipoapoptosis are features of non-alcoholic fatty liver disease. However, the mechanism by which FFAs mediate lipoapoptosis is unclear. Because JNK activation is pivotal in both the metabolic syndrome accompanying non-alcoholic fatty liver disease and cellular apoptosis, we examined the role of JNK activation in FFA-induced lipoapoptosis. Multiple hepatocyte cell lines and primary mouse hepatocytes were treated in culture with monounsaturated fatty acids and saturated fatty acids. Despite equal cellular steatosis, apoptosis and JNK activation were greater during exposure to saturated versus monounsaturated FFAs. Inhibition of JNK, pharmacologically as well as genetically, reduced saturated FFA-mediated hepatocyte lipoapoptosis. Cell death was caspase-dependent and associated with mitochondrial membrane depolarization and cytochrome c release indicating activation of the mitochondrial pathway of apoptosis. JNK-dependent lipoapoptosis was associated with activation of Bax, a known mediator of mitochondrial dysfunction. As JNK can activate Bim, a BH3 domain-only protein capable of binding to and activating Bax, its role in lipoapoptosis was also examined. Small interfering RNA-targeted knock-down of Bim attenuated both Bax activation and cell death. Collectively the data indicate that saturated FFAs induce JNK-dependent hepatocyte lipoapoptosis by activating the proapoptotic Bcl-2 proteins Bim and Bax, which trigger the mitochondrial apoptotic pathway.
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- "The clinical importance of NASH is related to its capacity to evolve in liver cirrhosis and cancer . The principal risk factor for the development of NASH is insulin resistance    that increases lipolysis and releases free fatty acids (FFA) causing liver injury    by excessive liver lipid accumulation. Oversupply of free fatty acids induces an increase in mitochondrial H 2 O 2 production that, in turn, oxidizes mitochondrial membranes and regulates activity of uncoupling protein 2 and carnitine palmitoyl transferase 1 . "
ABSTRACT: Liver steatosis can evolve to steatohepatitis (NASH) through a series of biochemical steps related to oxidative stress in hepatocytes. Antioxidants, such as silybin, have been proposed as a treatment of patients with nonalcoholic fatty liver disease (NAFLD) and NASH. In this study, we evaluated, in patients with histologically documented NASH, the oxidant/antioxidant status and lipid "fingerprint" in the serum of NASH patients, both in basal conditions and after 12 months of treatment with silybin-based food integrator Realsil (RA). The oxidant/antioxidant status analysis showed the presence of a group of patients with higher basal severity of disease (NAS scores 4.67 ± 2.5) and a second group corresponding to borderline NASH (NAS scores = 3.8 ± 1.5). The chronic treatment with RA changed the NAS score in both groups that reached the statistical significance only in group 2, in which there was also a significant decrease of serum lipid peroxidation. The lipidomic profile showed a lipid composition similar to that of healthy subjects with a restoration of the values of free cholesterol, lysoPC, SM, and PC only in group 2 of patients after treatment with RA. Conclusion. These data suggest that lipidomic and/or oxidative status of serum from patients with NASH could be useful as prognostic markers of response to an antioxidant treatment.Oxidative medicine and cellular longevity 06/2014; 2014:169216. DOI:10.1155/2014/169216 · 3.36 Impact Factor
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- "The cytotoxic response to elevated fatty acids appears to be specific to or made more severe by long-chain saturated fatty acids    . In hepatocytes, saturated fatty acids promote endoplasmic reticulum (ER) stress and apoptosis  , both of which are characteristic features of NAFLD  . The toxic effects of saturated fatty acids may be due to their inability, relative to unsaturated fatty acids, to be esterified and incorporated into triglyceride [7, 15–17]. "
ABSTRACT: Liver specific deletion of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) induces steatosis and hypersensitivity to insulin. Saturated fatty acids, which induce endoplasmic reticulum stress and cell death, appear to increase PTEN, whereas unsaturated fatty acids which do not induce endoplasmic reticulum stress or cell death reduce this protein. In the present study, the role of PTEN in saturated fatty acid-induced cytotoxicity was examined in H4IIE and HepG2 liver cells. Palmitate and stearate increased the expression of PTEN, whereas the unsaturated fatty acids, oleate and linoleate, reduced PTEN expression in both cell types. SiRNA-mediated knockdown of PTEN did not increase liver cell triglyceride stores or reduce palmitate- or stearate-mediated ER stress or apoptosis. These results suggest that PTEN does not play a significant role in saturated fatty acid-induced cytotoxicity in these liver cell models and in the absence of insulin.Journal of nutrition and metabolism 04/2013; 2013:514206. DOI:10.1155/2013/514206
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- "Extrinsic and intrinsic apoptosis as well as regulated necrosis (Fig. 1 and Supplementary Discussion) have been implicated in the death of hepatocytes as triggered by a variety of hepatotoxic insults such as viral and bacterial infections , metabolic disorders , alcohol overconsumption , and intoxication by xenobiotics . "
ABSTRACT: Inflammation can be either beneficial or detrimental for the liver, depending on multiple factors. Mild (i.e., limited in intensity and destined to resolved) inflammatory responses have indeed been shown to exert consistent hepatoprotective effects, contributing to tissue repair and promoting the reestablishment of homeostasis. Conversely, excessive (i.e., disproportionate in intensity and permanent) inflammation may induce a massive loss of hepatocytes and hence exacerbate the severity of various hepatic conditions, including ischemia-reperfusion injury, systemic metabolic alterations (e.g., obesity, diabetes, non-alcoholic fatty liver disorders), alcoholic hepatitis, intoxication by xenobiotics and infection, de facto being associated with irreversible liver damage, fibrosis and carcinogenesis. Both liver-resident cells (e.g., Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells) and cells that are recruited in response to injury (e.g., monocytes, macrophages, dendritic cells, natural killer cells) emit pro-inflammatory signals including - but not limited to - cytokines, chemokines, lipid messengers and reactive oxygen species that contribute to the apoptotic or necrotic demise of hepatocytes. In turn, dying hepatocytes release damage-associated molecular patterns that - upon binding to evolutionary conserved pattern recognition receptors - activate cells of the innate immune system to further stimulate inflammatory responses, resulting in the establishment of a highly hepatotoxic feedforward cycle of inflammation and cell death. In this review, we discuss the cellular and molecular mechanisms that account for the most deleterious effect of hepatic inflammation at the cellular level, that is, the initiation of a massive cell death response among hepatocytes.Journal of Hepatology 04/2013; 143(3). DOI:10.1016/j.jhep.2013.03.033 · 10.40 Impact Factor