The Alterations of Mitochondrial Function during NAFLD Progression-An Independent Effect of Mitochondrial ROS Production.

The progression of non-alcoholic fatty liver (NAFL) into non-alcoholic steatohepatitis implicates multiple mechanisms, chief of which is mitochondrial dysfunction. However, the sequence of events underlying mitochondrial failure are still poorly clarified. In this work, male C57BL/6J mice were fed with a high-fat plus high-sucrose diet for 16, 20, 22, and 24 weeks to induce NAFL. Up to the 20th week, an early mitochondrial remodeling with increased OXPHOS subunits levels and higher mitochondrial respiration occurred. Interestingly, a progressive loss of mitochondrial respiration along "Western diet" feeding was identified, accompanied by higher susceptibility to mitochondrial permeability transition pore opening. Importantly, our findings prove that mitochondrial alterations and subsequent impairment are independent of an excessive mitochondrial reactive oxygen species (ROS) generation, which was found to be progressively diminished along with disease progression. Instead, increased peroxisomal abundance and peroxisomal fatty acid oxidation-related pathway suggest that peroxisomes may contribute to hepatic ROS generation and oxidative damage, which may accelerate hepatic injury and disease progression. We show here for the first time the sequential events of mitochondrial alterations involved in non-alcoholic fatty liver disease (NAFLD) progression and demonstrate that mitochondrial ROS are not one of the first hits that cause NAFLD progression.

Severe hypoglycemia with reduced liver volume as an indicator of end-stage malnutrition in patients with anorexia nervosa: a retrospective observational study.

BACKGROUND: Hypophosphatemia due to excessive carbohydrate administration is considered the primary pathogenesis of refeeding syndrome. However, its association with liver injury and hypoglycemia, often seen in severe malnutrition before re-nutrition, remains unclear. Autophagy reportedly occurs in the liver of patients with severe malnutrition. This study aimed to clarify the pathophysiology of liver injury and hypoglycemia by focusing on liver volume. METHODS: Forty-eight patients with anorexia nervosa with a body mass index (BMI) of < 13 kg/m2 were included (median BMI: 10.51 kg/m2 on admission). Liver volume was measured in 36 patients who underwent abdominal computed tomography (CT), and the "estimated liver weight/ideal body weight" was used as the liver volume index. Seventeen blood test items were analyzed during the first 60 days. RESULTS: Liver volume significantly decreased when abdominal CTs were conducted shortly before or after hypoglycemia compared to when the scans were performed during periods without hypoglycemia. Five patients with severe hypoglycemia on days 13-18 after admission had a very low nutritional intake; of them, four showed a marked decrease in liver volume. Severe hypoglycemia was accompanied by low serum triglycerides and liver dysfunction. Patients experiencing hypoglycemia of blood glucose levels < 55 mg/dL (< 3.05 mmol/L) (32 patients; median lowest BMI: 9.45 kg/m2) exhibited significantly poorer blood findings for most of the 17 items, except serum phosphorus and potassium, than did those not experiencing hypoglycemia (16 patients; median lowest BMI: 11.2 kg/m2). All patients with a poor prognosis belonged to the hypoglycemia group. Empirically, initiating re-nutrition at 500 kcal/day (20-25 kcal/kg/day), increasing to 700-800 kcal/day after a week, and then gradually escalating can reduce serious complications following severe hypoglycemia. CONCLUSIONS: Liver volume reduction accompanied by hypoglycemia, low serum triglyceride levels, and liver dysfunction occurs when the body's stored energy sources are depleted and external nutritional intake is inadequate, suggesting that the liver was consumed as a last resort to obtain energy essential for daily survival. This pathophysiology, distinct from refeeding syndrome, indicates the terminal stage of malnutrition and is a risk factor for complications and poor prognosis. In treatment, extremely low nutrient levels should be avoided.

This study aimed to clarify the pathophysiology of severe malnutrition in patients with anorexia nervosa by focusing on liver volume. The small size of the liver was almost always accompanied by hypoglycemia within a week. In several cases, extremely low nutritional intake, continued for approximately 2 weeks after admission, resulted in severe hypoglycemia and a marked decrease in liver volume. The 32 patients with hypoglycemia presented worse blood test items related to liver function, nutrition, and blood cell count compared to the 16 patients without such a condition. All cases with poor prognosis were in the hypoglycemia group. These findings suggest that severe hypoglycemia with decreased liver volume indicates the end stage of malnutrition. Liver volume reduction is considered a reflection of the liver's consumption of itself as a last resort for energy procurement for daily survival when the body's stored energy sources are depleted, and external nutritional intake is insufficient. When managing such patients, extremely low nutritional administration should be avoided.

Sustained systemic inflammation increases autophagy and induces EMT/fibrotic changes in mouse liver cells: Protection by melatonin.

The unending lifestyle stressors along with genetic predisposition, environmental factors and infections have pushed the immune system into a state of constant activity, leading to unresolved inflammation and increased vulnerability to chronic diseases. Liver fibrosis, an early-stage liver condition that increases the risk of developing liver diseases like cirrhosis and hepatocellular carcinoma, is among the various diseases linked to inflammation that dominate worldwide morbidity and mortality. We developed a mouse model with low-grade lipopolysaccharide (LPS) exposure that shows hepatic damage and a pro-inflammatory condition in the liver. We show that inflammation and oxidative changes increase autophagy in liver cells, a degradation process critical in maintaining cellular homeostasis. Our findings from in vivo and in vitro studies also show that induction of both inflammation and autophagy trigger epithelial-mesenchymal transition (EMT) and pro-fibrotic changes in hepatocytes. Inhibiting the inflammatory pathways with a naturally occurring NF-κB inhibitor and antioxidant, melatonin, could assuage the changes in autophagy and activation of EMT/fibrotic pathways in hepatocytes. Taken together, this study shows a pathway linking inflammation and autophagy which could be targeted for future drug development to delay the progression of liver fibrosis.

Taurine attenuates liver autophagy and injury of offspring in gestational diabetic mellitus rats.

PURPOSE: Gestational diabetes mellitus (GDM) has many adverse effects on offspring, such as abnormal glycolipid metabolism, obesity, insulin resistance, mental retardation, schizophrenia and so on. METHODS: We established a GDM rat model by injecting 1% streptozotocin associated with a high-fat diet one week before pregnancy, and offspring rats were sacrificed at 8 weeks of age to obtain liver tissue for study. We used hematoxylin-eosin (HE) staining to observe liver morphological changes, Tunel staining for hepatocyte apoptosis, transmission electron microscope for liver ultrastructure, and western blot for protein expression in liver tissue. RESULTS: Compared with normal offspring rats, hepatocytes of GDM offspring rats showed obvious edema, liver organ index increased, and hepatocyte apoptosis and autophagosome in the liver were significantly increased; Bax, cleaved-caspase3/caspase3, LCII, Beclin 1, P-IKBα/IKBα and P-p65/p6 protein expression in the liver were significantly increased; Bcl2, p62 and PPARγ protein expression in the liver were significantly decreased. Tau prevented the GDM-related effects in the offspring: Tau decreased hepatocyte edema (or even disappears), liver organ index, hepatocyte apoptosis and the number of autophagosomes in the liver. In addition, Tau also decreased Bax, cleaved-caspase3/caspase3, LCII, Beclin 1, P-IKBα/IKBα and P-p65/p6 protein expression, and increased Bcl2, p62 and PPARγ protein expression in the liver of GDM offspring rats. CONCLUSION: Taurine should be considered as a potential gestational nutritional supplement to prevent liver damage in GDM offspring.