Acute Liver Cell Damage in Patients With Anorexia Nervosa: A Possible Role of Starvation-Induced Hepatocyte Autophagy
Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Hôpital Beaujon, AP-HP, Clichy, France. Gastroenterology
(Impact Factor: 16.72).
09/2008; 135(3):840-8, 848.e1-3. DOI: 10.1053/j.gastro.2008.05.055
Acute liver insufficiency is a rare complication of anorexia nervosa. The mechanisms for this complication are unclear. The aim of this study was to describe patient characteristics and clarify the mechanisms involved.
Liver specimens from 12 patients (median age, 24 years; median body mass index, 11.3 kg/m(2)), with a prothrombin index <50% and/or an International Normalized Ratio >1.7 and anorexia nervosa as the only cause for acute liver injury were analyzed. A detailed pathologic examination was performed, including under electron microscopy.
Liver cell glycogen depletion was a constant finding. There was a contrast between the increase in serum alanine aminotransferase (56 times normal on average; 1,904 IU/L) and the absence of significant hepatocyte necrosis on histology. Centrilobular changes (trabecular atrophy and/or sinusoidal fibrosis) were observed in 6 patients. There were rare or no (<5%) terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive hepatocytes, suggesting that apoptosis was not the primary mechanism. Hepatocytes from 4 patients showed numerous autophagosomes, a morphologic hallmark of autophagy, on electron microscopy. In contrast, the mitochondria, endoplasmic reticulum, and nuclei were normal in most cells. These features were absent in 11 control patients. The outcome was favorable in all patients, with a rapid return to normal liver function.
Anorexia nervosa with extremely poor nutritional status should be added to the list of conditions causing acute liver insufficiency. Our findings show that starvation-induced autophagy in the human liver may be involved in liver cell death during anorexia nervosa, even though other mechanisms of liver cell damage could also play a role.
Available from: scielo.br
- "For decades, dietary deficiencies were considered the major factor responsible for the development of liver disease in alcoholics (Korourian et al. 1999), because ethanol displaces normal nutrients, causing malnutrition (Liber 2004; Comporti et al. 2010). Moreover, it has been experimentally proved that nutritional deficiencies cause liver damage (Di Pascoli et al. 2004; Rautou et al. 2008; Caballero et al. 2011). Therefore, it was postulated that the combination of these factors cause ALD (Comporti et al. 2010). "
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ABSTRACT: Alcoholic liver disease is characterized by a wide spectrum of liver damage, which increases when ethanol is associated with high-fat diets (HFD). This work aimed to establish a model of alcoholic hepatic steatosis (AHS) by using a combination of 10% ethanol and sunflower seeds as the source of HFD. Male rats received water or 10% ethanol and regular chow diet and/or HFD, which consisted of sunflower seeds. The food consumption, liquid intake and body weight of the rats were monitored for 30 days. After this period, blood was collected for biochemical evaluation, and liver samples were collected for histological, mitochondrial enzyme activity and oxidative stress analyses. Our results indicated that the combination of 10% ethanol and HFD induced micro- and macrosteatosis and hepatocyte tumefaction, decreased the levels of reduced glutathione and glutathione S-transferase activity and increased the level of lipoperoxidation and superoxide dismutase activity. The mitochondrial oxidation of NADH and succinate were partially inhibited. Complexes I and II were the main inhibition sites. Hepatic steatosis was successfully induced after 4 weeks of the diet, and the liver function was modified. The combination of 10% ethanol and sunflower seeds as an HFD produced an inexpensive model to study AHS in rats.
Brazilian Archives of Biology and Technology 01/2015; 00(ahead):00-00. DOI:10.1590/S1516-8913201500294 · 0.55 Impact Factor
Available from: Christian Eugen Oberkofler
- "This seeming discrepancy may be explained by the re-elevation in serum HMGB1 and the reduction in intracellular HMGB1 aggregates after 2-d-relative to 1-d-fasting (considering that protection is lost upon concomitant HMGB1 injection into 1-d-fasted mice). Furthermore, human liver displays an accumulation of autophagosomes along with signs of increased cell permeability and elevations in liver enzymes following prolonged starvation . Analogously, we observed an increase in AST, ALT, and the cell death marker LDH in mouse liver fasted for two/three days compared to 1-d-fasted or unfasted mice (Supplementary Fig. 5). "
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ABSTRACT: Fasting and calorie restriction are associated with a prolonged life span and an increased resistance to stress. The protective effects of fasting have been exploited for the mitigation of ischemic organ injury, yet the underlying mechanisms remain incompletely understood. Here, we investigated whether fasting protects liver against ischemia reperfusion (IR) through energy-preserving or anti-inflammatory mechanisms.
Fasted C57BL6 mice were subjected to partial hepatic IR. Injury was assessed by liver enzymes and histology. Raw 264-7 macrophage-like cells were investigated in vitro. Sirt1 and Hmgb1 were inhibited using Ex527 and neutralizing antibodies, respectively.
Fasting for one, but not two or three days, protected from hepatic IR injury. None of the investigated energy parameters correlated with the protective effects. Instead, inflammatory responses were dampened in one-day-fasted mice and in starved macrophages. Fasting alone led to a reduction in circulating Hmgb1 associated with cytoplasmic Hmgb1 translocation, aggregate formation and autophagy. Inhibition of autophagy re-elevated circulating Hmgb1 and abolished protection in fasted mice, as did supplementation with Hmgb1. In vitro, Sirt1 inhibition prevented Hmgb1 translocation, leading to elevated Hmgb1 in the supernatant. In vivo, Sirt1 inhibition abrogated the fasting-induced protection, but had no effect in the presence of neutralizing Hmgb1 antibody.
Fasting for one day protects from hepatic IR injury via Sirt1-dependent downregulation of circulating Hmgb1. The reduction in serum Hmgb1 appears to be mediated by its engagement in the autophagic response. These findings integrate Sirt1, Hmgb1 and autophagy into a common framework that underlies the anti-inflammatory properties of short-term fasting.
Journal of Hepatology 04/2014; 61(2). DOI:10.1016/j.jhep.2014.04.010 · 11.34 Impact Factor
Available from: Meiju Äijälä
- "Usually, autophagy is considered as a protective mechanism , but hyperactive autophagy has also been reported in pathological conditions such as liver inflammation in a rat model of diabetes mellitus (Hagiwara et al. 2010) and as a possible cause of hepatocyte death in anorexia nervosa patients (Rautou et al. 2008) suggesting that both diminished or excessive autophagy could be deleterious. It has also been reported that leptin treatment might have unfavorable consequences via an overactivated leptin system and an SOCS3 inhibitory effect might lead to insulin resistance, hepatic steatosis and liver fibrosis (Polyzos et al. 2011). "
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ABSTRACT: Long-term fructose consumption has been shown to evoke leptin resistance, to elevate triglyceride levels and to induce insulin resistance and hepatic steatosis. Autophagy has been suggested to function in processes such as lipid storage in adipose tissue and inflammation in liver. Autophagy and the leptin system have also been suggested to regulate each other. This study aimed to identify the changes caused by fetal undernourishment and postnatal fructose diet in the gene expression of leptin, its receptors (LEPR-a, LEPR-b, LEPR-c, LEPR-e and LEPR-f) and autophagy genes in the white adipose tissue (WAT) and liver of adult male rats in order to clarify the mechanism behind the metabolic alterations. The data clearly revealed that the long-term postnatal fructose diet decreased leptin levels (p < 0.001), LEPR (p < 0.001), especially LEPR-b (p = 0.011) and LEPR-f (p = 0.005), as well as SOCS3 (p < 0.001), ACC (p = 0.006), ATG7 (p < 0.001), MAP1LC3β (p < 0.001) and LAMP2 (p = 0.004) mRNA expression in WAT. Furthermore, LEPR (p < 0.001), especially LEPR-b (p = 0.001) and LEPR-f (p < 0.001), ACC (p = 0.010), ATG7 (p = 0.024), MAP1LC3β (p = 0.003) and LAMP2 (p < 0.001) mRNA expression in the liver was increased in fructose-fed rats. In addition, the LEPR expression in liver and MAP1LC3β expression in WAT together explained 55.7 % of the variation in the plasma triglyceride levels of the rats (R adj. (2) = 0.557, p < 0.001). These results, together with increased p62 levels in WAT (p < 0.001), could indicate decreased adipose tissue lipid storing capacity as well as alterations in liver metabolism which may represent a plausible mechanism through which fructose consumption could disturb lipid metabolism and result in elevated triglyceride levels.
Genes & Nutrition 10/2013; 8(6). DOI:10.1007/s12263-013-0357-3 · 2.79 Impact Factor
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