• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.15 no.2
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• pp.74-78
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• 2012

With a markedly increased prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) now becomes the most common cause of chronic liver disease in both adults and children. The etiology and pathogenesis of NAFLD are multifactorial and remain incompletely understood. According to the "two-hit" theory, inflammatory cytokines and adipokines are activated by oxidative stress and they are involved in insulin resistance, necroinflammatory steatohepatitis and fibrosis. This review discusses the latest updates on the role of some of important inflammatory adipokines and cytokines in the pathogenesis of NAFLD with an emphasis on their potential therapeutic implications.

• BMB Reports
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• v.42 no.8
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• pp.475-481
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• 2009

Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease (AD). Insulin and insulin-like growth factors (IGFs) regulate neuronal survival, energy metabolism, and plasticity, which are required for learning and memory. Hence, endogenous brain-specific impairments in insulin and IGF signaling account for the majority of AD-associated abnormalities. However, a second major mechanism of cognitive impairment has been linked to obesity and Type 2 diabetes (T2DM). Human and experimental animal studies revealed that neurodegeneration associated with peripheral insulin resistance is likely effectuated via a liver-brain axis whereby toxic lipids, including ceramides, cross the blood brain barrier and cause brain insulin resistance, oxidative stress, neuro-inflammation, and cell death. In essence, there are dual mechanisms of brain insulin resistance leading to AD-type neurodegeneration: one mediated by endogenous, CNS factors; and the other, peripheral insulin resistance with excess cytotoxic ceramide production.

• BMB Reports
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• v.55 no.10
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• pp.481-487
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• 2022

Over the past few years, hydrogen sulfide (H₂S) has been shown to exert several biological functions in mammalian. The endogenous production of H₂S is mainly mediated by cystathione β-synthase, cystathione γ-lyase and 3-mercaptopyruvate sulfur transferase. These enzymes are broadly expressed in liver tissue and regulates liver function by working on a variety of molecular targets. As an important regulator of liver function, H₂S is critically involved in the pathogenesis of various liver diseases, such as non-alcoholic steatohepatitis and liver cancer. Targeting H₂S-generating enzymes may be a therapeutic strategy for controlling liver diseases. This review described the function of H₂S in liver disease and summarized recent characterized role of H₂S in several cellular process of the liver.

• Experimental and Molecular Medicine
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• v.50 no.12
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• pp.2.1-2.12
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• 2018

Glucagon-like peptide-1 (GLP-1) has a broad spectrum of biological activity by regulating metabolic processes via both the direct activation of the class B family of G protein-coupled receptors and indirect nonreceptor-mediated pathways. GLP-1 receptor (GLP-1R) agonists have significant therapeutic effects on non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in animal models. However, clinical studies indicated that GLP-1 treatment had little effect on hepatic steatosis in some NAFLD patients, suggesting that GLP-1 resistance may occur in these patients. It is well-known that the gut metabolite sodium butyrate (NaB) could promote GLP-1 secretion from intestinal L cells. However, it is unclear whether NaB improves hepatic GLP-1 responsiveness in NAFLD. In the current study, we showed that the serum GLP-1 levels of NAFLD patients were similar to those of normal controls, but hepatic GLP-1R expression was significantly downregulated in NAFLD patients. Similarly, in the NAFLD mouse model, mice fed with a high-fat diet showed reduced hepatic GLP-1R expression, which was reversed by NaB treatment and accompanied by markedly alleviated liver steatosis. In addition, NaB treatment also upregulated the hepatic p-AMPK/p-ACC and insulin receptor/insulin receptor substrate-1 expression levels. Furthermore, NaB-enhanced GLP-1R expression in HepG2 cells by inhibiting histone deacetylase-2 independent of GPR43/GPR109a. These results indicate that NaB is able to prevent the progression of NAFL to NASH via promoting hepatic GLP-1R expression. NaB is a GLP-1 sensitizer and represents a potential therapeutic adjuvant to prevent NAFL progression to NASH.

• Health Policy and Management
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• v.31 no.4
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• pp.472-478
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• 2021

Background: Early identification of patients who are highly likely to develop severe illness among confirmed cases of coronavirus disease 19 (COVID-19) can be expected to lead to effective treatment. This study therefore aimed to determine whether the presence of nonalcoholic fatty liver disease (NAFLD) has an impact on the exacerbation of COVID-19 symptoms. Methods: The study used the Korean National Health Insurance claim data for treatment of COVID-19 patients in 2020. NAFLD includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The outcome variables used were hospitalization and the use of medical devices. Hospitalization was defined by a length of stay exceeding one day and the use of medical devices was defined as one or more uses of a ventilator or extracorporeal membrane oxygenation. Multivariable logistic regression analysis was performed to determine if there was a difference in the hospitalization and use of medical devices of COVID-19 patients depending on the presence of NAFLD. Results: The odds ratio of hospitalization was 1.059, indicating slightly higher odds of hospitalization for patients with NAFL or NASH compared to those without the conditions, but it was not statistically significant (0.969-1.156). On the other hand, the odds ratio of use of medical devices was high at 1.667 and was statistically significant (1.111-2.501). Conclusion: The study results found NAFLD to be a risk factor that can exacerbate symptoms in COVID-19 patients. Accordingly, it is necessary to identify NAFLD patients through preemptive screening and provide them with appropriate treatments.

• The Journal of Internal Korean Medicine
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• v.43 no.4
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• pp.606-624
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• 2022

Objective: The aim of this study was to compare the effects of different doses of Geumnyeonyijin-tang (GNYJT) water extracts with those of metformin (250 mg/kg) in mild diabetic-obese mice. Methods and Results: The 48 mice were divided into 1 normal pellet diet (NFD) group and 5 high-fat diet (HFD) groups. At the end of 12 weeks of oral administration of metformin (250 mg/kg) or GNYJT water extracts (400, 200, or100 mg/kg), the effects were evaluated. The HFD control mice showed noticeable increases in body weight, adipose tissue density, fat pad weight of the periovarian and abdominal wall, and insulin, blood glucose, and HbA1c levels, with decreases in serum HDL levels. Increases in the periovarian and dorsal abdominal fat pad, regions of steatohepatitis, adipocyte hypertrophy, and hepatocyte hypertrophy were also discovered. The HFD group showed a decline in glucose levels and elevation of hepatic gluconeogenesis, suggesting an HFD-induced AMPK downregulation related to glucose dysregulation, as well as lipid metabolism related to obese insulin-resistant type II diabetes, dyslipidemia, and oxidative stress related diabetic hepatopathy (non-alcoholic fatty liver disease, NAFLD). Conclusion: Assessment of the key parameters for inhibition of diabetes and related complications in HFD-fed diabetic-obese mice demonstrated that GNYJT water extracts have favorable ameliorating effects. The effect of GNYJT was manifested through the stimulation of AMPK upregulation of related hepatic glucose enzyme activities and expression of lipid metabolism-related genes. Therefore, appropriate oral dosages of GNYJT could be promising as a new preventive candidate for controlling diabetes and related complications. Further screening of biologically active compounds, elucidation of detailed mechanisms, and more animal studies are warranted.

• Molecules and Cells
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• v.46 no.8
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• pp.496-512
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• 2023

A fructose-enriched diet is thought to contribute to hepatic injury in developing non-alcoholic steatohepatitis (NASH). However, the cellular mechanism of fructose-induced hepatic damage remains poorly understood. This study aimed to determine whether fructose induces cell death in primary hepatocytes, and if so, to establish the underlying cellular mechanisms. Our results revealed that treatment with high fructose concentrations for 48 h induced mitochondria-mediated apoptotic death in mouse primary hepatocytes (MPHs). Endoplasmic reticulum stress responses were involved in fructose-induced death as the levels of phosho-eIF2α, phospho-C-Jun-N-terminal kinase (JNK), and C/EBP homologous protein (CHOP) increased, and a chemical chaperone tauroursodeoxycholic acid (TUDCA) prevented cell death. The impaired oxidation metabolism of fatty acids was also possibly involved in the fructose-induced toxicity as treatment with an AMP-activated kinase (AMPK) activator and a PPAR-α agonist significantly protected against fructose-induced death, while carnitine palmitoyl transferase I inhibitor exacerbated the toxicity. However, uric acid-mediated toxicity was not involved in fructose-induced death as uric acid was not toxic to MPHs, and the inhibition of xanthine oxidase (a key enzyme in uric acid synthesis) did not affect cell death. On the other hand, treatment with inhibitors of the nicotinamide adenine dinucleotide (NAD)⁺-consuming enzyme CD38 or CD38 gene knockdown significantly protected against fructose-induced toxicity in MPHs, and fructose treatment increased CD38 levels. These data suggest that CD38 upregulation plays a role in hepatic injury in the fructose-enriched diet-mediated NASH. Thus, CD38 inhibition may be a promising therapeutic strategy to prevent fructose-enriched diet-mediated NASH.

• Korean Journal of Clinical Laboratory Science
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• v.47 no.4
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• pp.251-258
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• 2015

Curcumin, a major polyphenolic compound of turmeric, is well known to prevent non-alcoholic steatohepatitis (NASH) related to obesity. The aim of the study was to investigate the effect of curcumin on hepatic fibrosis induced by carbon tetrachloride ($CCl_4$) in obese mice. $CCl_4$ was administrated in mice fed a normal diet (ND) or a high fat diet (HFD) for 7 weeks together with or without curcumin. It was conducted to examine for metabolic profiles, adipocyte size, and liver fibrosis by serum biochemistry, histology and immunohistochemistry. Also, Apoptosis of hepatic cells was determined by the TUNEL method. Treatment with curcumin significantly lowered the body weight, fasting glucose, serum AST and ALT, and decreased the adipocyte size, the number of macrophage and mast cells in adipose tissue, and collagen deposition in liver tissue in the HFD+$CCl_4$ group compared with the findings of the HFD+$CCl_4$ group. In contrast, treatment with curcumin on the ND+$CCl_4$ group did not show a significant difference except the body weight and mast cell number when compared with the ND+$CCl_4$ group. Furthermore, curcumin significantly reduced the number of parenchymal apoptotic cells, whereas it increased the number of non-parenchymal apoptotic cells, especially resembling an activated hepatic stellate cell in the liver. Taken together, this data suggests that curcumin might be an effective antifibrotic drug for the prevention of liver disease progression in obese mice. Thus, the development of curcumin as a therapy for obesity and liver fibrosis is supported.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.13 no.1
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• pp.51-57
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• 2010

Purpose: It has been reported that children with hypopituitarism have features of metabolic syndrome, including obesity, impaired glucose tolerance, and dyslipidemia. The aim of this study was to investigate the clinical features and liver histology of pediatric non-alcoholic fatty liver disease (NAFLD) associated with hypopituitarism. Methods: We reviewed the clinical data of 11 children diagnosed with NAFLD among patients with hypopituitarism. Results: The mean age at the time of diagnosis of hypopituitarism was 10.4${\pm}$3.2 years, and the mean age at the time of diagnosis of NAFLD was 13.1${\pm}$2.7 years. A craniopharyngioma was the most common cause of pituitary dysfunction. At the time of diagnosis of NAFLD, 9 patients (82%) had a body mass index greater than the 85th percentile, 5 patients (45%) had elevated fasting blood glucose levels, and 9 patients (82%) had hypertriglyceridemia. The mean height SD score was significantly lower at the time of diagnosis of NAFLD than at the time of diagnosis of hypopituitarism. Of the six patients who were biopsied, one had cirrhosis, two had non-alcoholic steatohepatitis (NASH) with bridging fibrosis, two had NASH with mild portal fibrosis, and one had simple steatosis. Conclusion: Children with hypopituitarism are at risk of short stature, obesity, dyslipidemia, and NAFLD. The early diagnosis of NAFLD is important in children with hypopituitarism because advanced fibrosis is common.