Mechanisms of Lipotoxicity in NAFLD and Clinical Implications

Division of Pediatric Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN, USA.
Journal of pediatric gastroenterology and nutrition (Impact Factor: 2.63). 05/2011; 53(2):131-40. DOI: 10.1097/MPG.0b013e31822578db
Source: PubMed


With the epidemic of childhood obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in pediatrics. NAFLD is strongly associated with insulin resistance and increased level of serum free fatty acids (FFAs). FFAs have direct hepatotoxicity through the induction of an endoplasmic reticulum stress response and subsequently activation of the mitochondrial pathway of cell death. FFAs may also result in lysosomal dysfunction and alter death receptor gene expression. Lipoapoptosis is a key pathogenic process in NAFLD, and correlates with progressive inflammation, and fibrosis. Accumulation of triglyceride in the liver results from uptake and esterification of FFAs by the hepatocyte, and is less likely to be hepatotoxic per se. To date, there are no proven effective therapies that halt NAFLD progression or unfortunately improve prognosis in children. The cellular mechanisms of lipotoxicity are complex but provide potential therapeutic targets for NAFLD. In this review we discuss several potential therapeutic opportunities in detail including inhibition of apoptosis, c-Jun-N-terminal kinase, and endoplasmic reticulum stress pathways.

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    • "One of the metabolic syndromes associated with exposure to BPA is nonalcoholic fatty liver disease (NAFLD). It is the most prevalent liver disease worldwide in pediatric patients with more than 10% of children and adolescents affected in industrialized countries (Greco et al., 2008; Ibrahim et al., 2011). NAFLD comprises steatohepatitis (NASH) and other liver diseases such as steatosis. "
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    ABSTRACT: For several decades, people have been in contact with bisphenol A (BPA) primarily through their diet. Nowadays it is gradually replaced by an analogue, bisphenol S (BPS). In this study, we compared the effects of these two bisphenols in parallel with the positive control diethylstilbestrol (DES) on different hepatocyte cell lines. Using a cellular impedance system we have shown that BPS is less cytotoxic than BPA in acute and chronic conditions. We have also demonstrated that, contrary to BPA, BPS is not able to induce an increase in intracellular lipid and does not activate the PXR receptor which is known to be involved in part, in this process. In parallel, it failed to modulate the expression of CYP3A4 and CYP2B6, the drug transporter ABCB1 and other lipid metabolism genes (FASN, PLIN). However, it appears to have a weak effect on GSTA4 protein expression and on the Erk1/2 pathway. In conclusion, in contrast to BPA, BPS does not appear to induce the metabolic syndrome that may lead to non-alcoholic fatty liver disease (NAFLD), in vitro. Although we have to pay special attention to BPS, its use could be less dangerous concerning this toxicological endpoint for human health.
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    • "When the mechanisms that protect hepatocytes from FFA-mediated lipotoxicity become overwhelmed, hepatic steatosis progresses to develop more advanced liver disease [25]. This protective mechanism may explain why 23% of the NAFLD subjects had evidence of NASH, whereas fibrosis and cirrhosis were observed in 20% of NASH patients, while only 9% had liver failure and 1% had HCC [24] [25]. Previous studies indicated that HPS regulates cell fate and shows a protect effect on CCl 4 -induced liver injury. "
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    ABSTRACT: Background & aims: While non-alcoholic fatty liver disease (NAFLD) is the most common risk factor of chronic liver disease, the mechanisms that initiate its development are obscure. Hepassocin (HPS) is a hepatokine that has been reported to be involved in liver regeneration. In addition to the mitogenic activity of HPS, HPS expression is decreased in patients with hepatoma. However, the role of HPS in NAFLD is still unknown. Methods: A total of 393 subjects with (n=194) or without (n=199) NAFLD were enrolled to evaluate the serum HPS concentration. In order to clarify the causal inference between HPS and NAFLD, we used experimental animal and cell models. Hepatic overexpression or silencing of HPS was achieved by lentiviral vector delivery in mice and lipofectamine transfection in HepG2 cells. Lipogenesis related proteins were detected by Western blots. The expression of inflammatory factors was determined by real-time polymerase chain reaction. Results: Subjects with NAFLD had a higher serum HPS concentration than those without it. Overexpression of HPS increased hepatic lipid accumulation and NAFLD activity scores (NAS), whereas deletion of HPS improved high fat diet-induced hepatic steatosis and decreased NAS in mice. Additionally, oleic acid, a steatogenic reagent, increased HPS expression in hepatocytes. Furthermore, overexpression of HPS in HepG2 cells induced lipid accumulation through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent pathway, whereas deletion of HPS decreased oleic acid-induced lipid accumulation. Conclusions: The present study provides evidence that HPS plays an important role in NAFLD and induces hepatic lipid accumulation through an ERK1/2-dependent pathway.
    Full-text · Article · Jun 2013 · Journal of Hepatology
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    • "The extrinsic pathway is induced by death ligands such as Fas (a key death receptor belonging to the tumor-necrosis-factor- (TNF-) receptor family) and TRAIL (TNF-related apoptosis-inducing ligand). In contrast, the intrinsic pathway of cell death is activated by the intracellular stress of membrane-bound organelles, such as ER, lysosomes, and mitochondria [43]. "
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    ABSTRACT: The ingestion of excessive amounts of saturated fatty acids (SFAs) and transfatty acids (TFAs) is considered to be a risk factor for cardiovascular diseases, insulin resistance, dyslipidemia, and obesity. The focus of this paper was to elucidate the influence of dietary SFA and TFA intake on the promotion of lipotoxicity to the liver and cardiovascular, endothelial, and gut microbiota systems, as well as on insulin resistance and endoplasmic reticulum stress. The saturated and transfatty acids favor a proinflammatory state leading to insulin resistance. These fatty acids can be involved in several inflammatory pathways, contributing to disease progression in chronic inflammation, autoimmunity, allergy, cancer, atherosclerosis, hypertension, and heart hypertrophy as well as other metabolic and degenerative diseases. As a consequence, lipotoxicity may occur in several target organs by direct effects, represented by inflammation pathways, and through indirect effects, including an important alteration in the gut microbiota associated with endotoxemia. Interactions between these pathways may perpetuate a feedback process that exacerbates an inflammatory state. The importance of lifestyle modification, including an improved diet, is recommended as a strategy for treatment of these diseases.
    Full-text · Article · Jan 2013 · Mediators of Inflammation
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