• Molecules and Cells
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• v.45 no.5
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• pp.343-352
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• 2022

The advent of the assay for transposase-accessible chromatin using sequencing (ATAC-seq) has shown great potential as a leading method for analyzing the genome-wide profiling of chromatin accessibility. A comprehensive reference to the ATAC-seq dataset for disease progression is important for understanding the regulatory specificity caused by genetic or epigenetic changes. In this study, we present a genome-wide chromatin accessibility profile of 44 liver samples spanning the full histological spectrum of nonalcoholic fatty liver disease (NAFLD). We analyzed the ATAC-seq signal enrichment, fragment size distribution, and correlation coefficients according to the histological severity of NAFLD (healthy control vs steatosis vs fibrotic nonalcoholic steatohepatitis), demonstrating the high quality of the dataset. Consequently, 112,303 merged regions (genomic regions containing one or multiple overlapping peak regions) were identified. Additionally, we found differentially accessible regions (DARs) and performed transcription factor binding motif enrichment analysis and de novo motif analysis to determine new biomarker candidates. These data revealed the gene-regulatory interactions and noncoding factors that can affect NAFLD progression. In summary, our study provides a valuable resource for the human epigenome by applying an advanced approach to facilitate diagnosis and treatment by understanding the non-coding genome of NAFLD.

• East Asian mathematical journal
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• v.36 no.3
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• pp.365-376
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• 2020

Nonalcoholic fatty liver is a type of fatty liver in which fat accumulates in the liver without alcohol. In the accumulation, Nrf1 and miR-378 genes play very important role, so called negative feedback loop, in which the two genes suppress the other's production. In other words, Nrf1 activates fatty acid oxidation which promotes fat consumption in the liver, while miR-378 deactivates fatty acid oxidation. Thus, both genes regulate nonalcoholic fatty liver. In this paper, the negative feedback loop of Nrf1 and miR-378 are expressed by a system of ordinary differential equations. And, bifurcation simulation shows the change in the amount of each gene with significant parameter range changes. Bifurcation simulation has also used to determine the thresholds for transit between disease and steady state.

• IMMUNE NETWORK
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• v.16 no.3
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• pp.147-158
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• 2016

The liver lies at the intersection of multiple metabolic pathways and consequently plays a central role in lipid metabolism. Pathological disturbances in hepatic lipid metabolism are characteristic of chronic metabolic diseases, such as obesity-mediated insulin resistance, which can result in nonalcoholic fatty liver disease (NAFLD). Tissue damage induced in NAFLD activates and recruits liver-resident and non-resident immune cells, resulting in nonalcoholic steatohepatitis (NASH). Importantly, NASH is associated with an increased risk of significant clinical sequelae such as cirrhosis, cardiovascular diseases, and malignancies. In this review, we describe the immunopathogenesis of NASH by defining the known functions of immune cells in the progression and resolution of disease.

• The Journal of Internal Korean Medicine
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• v.30 no.2
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• pp.365-374
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• 2009

Objectives : The aim of this study was to investigate the effects of Gamisaenggan-tang on high fat diet induced nonalcoholic fatty liver disease. Methods: Rats were randomly divided into four groups. The Normal group was fed a solid diet containing 10% fat. The Gamisaenggan-tang (GS) group was fed a solid diet containing 10% fat and Gamisaenggan-tang (90mg/100g body weight). The Control group was fed a solid diet containing 60% fat. The HFD-Gamisaenggan-tang (HFD-GS) group was fed a solid diet containing 60% fat and Gamisaenggan-tang (90mg/100g body weight). Six weeks later, rats body weight, liver weight, serum ALT, GGT, ALP levels were measured. Histological findings (Oil red O staining), hepatic triglyceride, TNF-${\alpha}$, and TGF-${\beta}$ levels in the liver tissue were studied. Results: Average body weight of the HFD-GS group was significantly less than that of the Control group. There were no significant liver weight differences among each group. The GGT levels of the HFD-GS group were significantly less than those of the Control group. However, there were no significant differences in the ALT or ALP levels among the groups. TNF-${\alpha}$ protein production assessed by western blot analysis was reduced by Gamisaenggan-tang. Greater fat accumulation was observed in the liver tissue of the Control group than in the HFD-GS group, which means the Gamisaenggan-tang has an inhibitory effect on the accumulation of fat in the liver. Conclusion : The results suggest that Gamisaenggan-tang can be potential candidate for the treatment of nonalcoholic fatty liver disease in clinics.

• The Korean Journal of Food And Nutrition
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• v.35 no.5
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• pp.332-342
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• 2022

Nonalcoholic fatty liver disease (NAFLD) is recognized one of the leading metabolic diseases globally, and the younger age population with the disease is rapidly growing, especially in developed countries. Since there has been no approved medicine, losing weight is known to be the only best remedy to control or reverse the disease. Recently, the field of microbiome has attracted much attention to offer more practical choices for patients. Here, we provide experimental evidence that Streptococcus thermophilus LM1012 (LM1012), a safe probiotic strain, is effective for improving NAFLD indexes. In the methionine-choline deficient (MCD) diet induced C57BL/6 mouse model, administration of LM1012 promoted marked reductions of aspartate transaminase (23.8%), total bilirubin (27.8%), hydroxycholesterol (64.2%), triglyceride (29.7%) and IL-1β (68.3%) compared to the MCD diet alone group. Also, the histopathological data imply that LM1012 inhibited fat accumulation and inflammation in the liver, which are the key biomarkers for progression of the disease. Together, these findings suggest that human consumption of LM1012 as a healthy nutritional supplement, may be helpful in reducing the risk of liver damages in NAFLD patients.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.24 no.3
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• pp.295-305
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• 2021

Purpose: Hepcidin levels have previously been reported to be correlated with liver damage. However, the association between hepcidin levels and liver fibrosis in children with fatty liver disease remains unclear. This study therefore aimed to investigate the pathophysiology of fibrosis in children with fatty liver disease and its association with hepcidin levels. Methods: This retrospective case series included 12 boys aged 6-17 years who were diagnosed with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) at the Tokyo Medical University Hospital. Sixteen liver biopsy samples from 12 subjects were analyzed. Serum hepcidin levels were assayed using enzyme-linked immunosorbent assay. Immunostaining for hepcidin was performed, and the samples were stratified by staining intensity. Results: Serum hepcidin levels were higher in pediatric NAFLD/NASH patients than in controls. Conversely, a significant inverse correlation was observed between hepcidin immunostaining and Brunt grade scores and between hepcidin scores and gamma-glutamyltranspeptidase, hyaluronic acid, and leukocyte levels. We observed inverse correlations with a high correlation coefficient of >0.4 between hepcidin immunostaining and aspartate aminotransferase, alanine aminotransferase, total bile acid, and platelet count. Conclusion: There was a significant inverse correlation between hepcidin immunoreactivity and fibrosis in pediatric NAFLD patients; however, serum hepcidin levels were significantly higher, suggesting that these patients experienced a reduction in the hepcidin-producing ability of the liver in response to iron levels, leading to subsequent fibrosis. Therefore, hepcidin levels can be used as markers to identify the progression of fibrosis in patients with NAFLD.

• 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.

• The Journal of Internal Korean Medicine
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• v.43 no.4
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• pp.680-719
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• 2022

Objectives: The aim of this study was to investigate the trends in research on non-alcoholic fatty liver disease (NAFLD) using Korean traditional medicine. Methods: This review included studies related to the treatment of NAFLD, irrespective of the year of publication. The search terms were "nonalcoholic fatty liver disease", "non-alcoholic fatty liver", "nonalcoholic hepatitis", "herb", "herbal medicine", "acupuncture", and "traditional medicine". The studies were analyzed according to the type of research. Results: After screening, 179 studies were selected from the 592 identified by the search. The types of studies were 151 in vivo or in vitro studies, 5 randomized controlled trials, 12 case reports, 2 unspecified clinical studies, 8 review articles, and 1 article that was difficult to classify. Conclusion: Analysis of the trends in Korean traditional medicine treatment by reviewing the studies on NAFLD revealed a focus on experimental studies rather than clinical studies. Therefore, multifaceted and well-designed studies are needed.

• Journal of Preventive Medicine and Public Health
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• v.41 no.6
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• pp.407-412
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• 2008

Objectives: The purpose of this study was to evaluate the relationship of nonalcoholic fatty liver and cardiovascular risk factors. Methods: This study was conducted to investigate the association of nonalcoholic fatty liver and cardiovascular risk factors for adult men (n=2976) and women (n=2442) who were over 19 years old, after excluding the HBsAg(+) or anti-HCV(+) patients and the men and women with increased alcohol intake (men: 40g/week, women: 20g/week). Results: Compared with the normal liver subjects, the nonalcoholic fatty liver subjects showed a significantly increased frequency of abnormal systolic blood pressure (${geq}120mmHg$), fasting blood sugar (${\geq}100mg/dL$), total cholesterol ($({\geq}200 mg/dL$), triglyceride ($({\geq}150mg/dL$), high density lipoprotein cholesterol (<40 mg/dL), low density lipoprotein cholesterol ($({\geq}130g\; m/dL$) and abdominal obesity in men, and all these measures were significantly increased in the women except for abnormal HDL cholesterol. After adjusting for the body mass index, age, smoking, exercise and a nonalcoholic liver, the odds ratios of an abnormal waist hip ratio were 1.35(95% Confidence Interval=1.05-4.72) in the mild fatty liver, 1.61 (1.19-2.18) in the moderate fatty liver, 2.77(1.57-4.92) in the severe fatty liver compared with a normal liver. The adjusted odds ratios for abnormal fasting blood sugar were 1.26(1.03-1.53) in the mild fatty liver, 1.62(1.27-2.06) in the moderate fatty Iiver and 1.77(1.12-2.78) in the severe fatty liver. The adjusted odds ratios for abnormal triglyceride were 1.38(1.11-1.72) in the mild fatty liver, 1.73(0.33-2.24) in the moderate fatty liver and 1.91 (1.17-3.10) in the severe fatty liver of men. Adjusted odds ratios for abnormal triglyceride were 1.50(1.04-2.15) in mild, 1.71(1.07-2.68) in moderate, 1.81(0.69-4.38) in severe fatty liver of women. Conclusions: The nonalcoholic fatty liver subjects had more cardiovascular risk factors compared with the normal liver subjects. Thus, prevention and treatment of the nonalcoholic fatty liver is necessary by lifestyle modifications such as restriction of alcohol intake, no smoking, exercise and adequate eating habits.

• Journal of Nutrition and Health
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• v.36 no.6
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• pp.577-588
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• 2003

Severe protein-calorie malnutrition, common in patients with advanced liver disease, can seriously undermine the capacity for regeneration and functional restoration of liver. Nutritional supplementation for these patients can improve biochemical and hormonal abnormalities. However, these effects were not identified in patient with nonalcoholic liver cirrhosis. To determine effects of nutritional supplementation in patients with nonalcoholic liver cirrhosis, 77 subjects aged 29 to 69 years participated in this study for 12 weeks and were subdivided into three groups; normal diet group (Control group, n ＝ 16), branched-chain amino acid supplementation group (BCAA group, n ＝ 31), nutritional supplementation group (NS group, n ＝ 30). Anthropometric parameters, hemoglobin, hematocrit, blood cell counts, serum levels of lipids, vitamins, minerals and fatty acid composition, and plasma amino acids were examined. The mean values of age and height, and the initial values of weight and body mass index (BMI) were not different among all groups. After 12 weeks, there were no significant changes in these values in Control group. Only NS group showed significant increases in weight, lean body mass, midarm circumference, triceps skinfold thickness. Serum transferrins were increased both in BCAA and NS groups. Plasma levels of branched-chain amino acids, urea amino acids and glutamic acid were also significantly increased in these groups, but plasma levels of ammonia, serum LDL cholesterol and atherogenic index were decreased. However, there were no significant changes in serum levels of vitamin and mineral and composition of fatty acids in phospholipids in these groups. These results showed that the nutritional supplementation for patients with nonalcoholic liver cirrhosis can more improve nutritional status in these people together with increases of weight, body fat and lean body mass, compared to only BCAA supplementation. To ascertain and investigate the appropriate nutritional supplementation for patients with nonalcoholic liver cirrhosis, further studies are necessary.