• Nutrition Research and Practice
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• v.17 no.1
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• pp.13-31
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• 2023

BACKGROUND/OBJECTIVES: Epigenetic regulation by nutrients can influence the development of specific diseases. This study sought to examine the effect of individual nutrients and nutrient families in the context of preventing chronic metabolic diseases via epigenetic regulation. The inhibition of lipid accumulation and inflammation by nutrients including proteins, lipids, vitamins, and minerals were observed, and histone acetylation by histone acetyltransferase (HAT) was measured. Correlative analyses were also performed. MATERIALS/METHODS: Nutrients were selected according to information from the Korean Ministry of Food and Drug Safety. Selected nutrient functionalities, including the attenuation of fatty acid-induced lipid accumulation and lipopolysaccharide-mediated acute inflammation were evaluated in mouse macrophage Raw264.7 and mouse hepatocyte AML-12 cells. Effects of the selected nutrients on in vitro HAT inhibition were also evaluated. RESULTS: Nitric oxide (NO) production correlated with HAT activity, which was regulated by the amino acids group, suggesting that amino acids potentially contribute to the attenuation of NO production via the inhibition of HAT activity. Unsaturated fatty acids tended to attenuate inflammation by inhibiting NO production, which may be attributable to the inhibition of in vitro HAT activity. In contrast to water-soluble vitamins, the lipid-soluble vitamins significantly decreased NO production. Water- and lipid-soluble vitamins both exhibited significant inhibitory activities against HAT. In addition, calcium and manganese significantly inhibited lipid accumulation, NO production, and HAT activity. CONCLUSIONS: Several candidate nutrients and their family members may have roles in the prevention of diseases, including hepatic steatosis and inflammation-related diseases (i.e., nonalcoholic steatohepatitis) via epigenetic regulation. Further studies are warranted to determine which specific amino acids, unsaturated fatty acids and lipid-soluble vitamins or specific minerals influence the development of steatosis and inflammatory-related diseases.

• 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.

• Biomolecules & Therapeutics
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• v.31 no.1
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• pp.40-47
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• 2023

Activation of the NLRP3 inflammasome is a necessary process to induce fibrosis in nonalcoholic fatty liver disease (NAFLD). Nonalcoholic steatohepatitis (NASH) is a kind of NAFLD that encompasses the spectrum of liver disease. It is characterized by inflammation and ballooning of hepatocytes during steatosis. We tested whether inhibiting the NLRP3 inflammasome could prevent the development and pathology of NASH. We identified loganin as an inhibitor of the NLRP3 inflammasome and investigated whether in vivo administration of loganin prevented NASH symptoms using a methionine-choline deficient (MCD) diet model in mice. We found that loganin inhibited the NLRP3 inflammasome activation triggered by ATP or nigericin, as shown by suppression of the production of interleukin (IL)-1β and caspase-1 (p10) in mouse primary macrophages. The speck formation of apoptosisassociated speck-like protein containing a caspase recruitment domain (ASC) was blocked by loganin, showing that the assembly of the NLRP3 inflammasome complex was impaired by loganin. Administration of loganin reduced the clinical signs of NASH in mice fed the MCD diet, including hepatic inflammation, fat accumulation, and fibrosis. In addition, loganin reduced the expression of NLRP3 inflammasome components in the liver. Our findings indicate that loganin alleviates the inflammatory symptoms associated with NASH, presumably by inhibiting NLRP3 inflammasome activation. In summary, these findings imply that loganin may be a novel nutritional and therapeutic treatment for NASH-related inflammation.

• Journal of Ginseng Research
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• v.48 no.1
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• pp.89-97
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• 2024

Background: Ginsenoside F2 (GF2), the protopanaxadiol-type constituent in Panax ginseng, has been reported to attenuate metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanism of action is not fully understood. Here, this study investigates the molecular mechanism by which GF2 regulates MASLD progression through liver X receptor (LXR). Methods: To demonstrate the effect of GF2 on LXR activity, computational modeling of protein-ligand binding, Time-resolved fluorescence resonance energy transfer (TR-FRET) assay for LXR cofactor recruitment, and luciferase reporter assay were performed. LXR agonist T0901317 was used for LXR activation in hepatocytes and macrophages. MASLD was induced by high-fat diet (HFD) feeding with or without GF2 administration in WT and LXRα^-/- mice. Results: Computational modeling showed that GF2 had a high affinity with LXRα. LXRE-luciferase reporter assay with amino acid substitution at the predicted ligand binding site revealed that the S264 residue of LXRα was the crucial interaction site of GF2. TR-FRET assay demonstrated that GF2 suppressed LXRα activity by favoring the binding of corepressors to LXRα while inhibiting the accessibility of coactivators. In vitro, GF2 treatments reduced T0901317-induced fat accumulation and pro-inflammatory cytokine expression in hepatocytes and macrophages, respectively. Consistently, GF2 administration ameliorated hepatic steatohepatitis and improved glucose or insulin tolerance in WT but not in LXRα^-/- mice. Conclusion: GF2 alters the binding affinities of LXRα coregulators, thereby interrupting hepatic steatosis and inflammation in macrophages. Therefore, we propose that GF2 might be a potential therapeutic agent for the intervention in patients with MASLD.

• Annals of Hepato-Biliary-Pancreatic Surgery
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• v.26 no.1
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• pp.69-75
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• 2022

Backgrounds/Aims: Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease requiring liver transplantation (LT). The objective of this study was to investigate the clinicopathological features and posttransplant courses of seven LT recipients with PFIC. Methods: This was a retrospective single-center study of patients with PFIC who underwent LT from January 2013 to June 2020. Results: Two and five patients were diagnosed with PFIC type 1 and type 2, respectively. For all seven patients, age of PFIC onset was at birth. Jaundice was present in all cases. Mean pretransplant total and direct bilirubin levels were 16.1 ± 8.1 mg/dL and 12.4 ± 6.2 mg/dL, respectively. Median patient age and body weight at LT were 10 months and 7 kg, respectively. Types of donors were mothers of patients in four and deceased donors in three. All five patients with PFIC type 2 recovered uneventfully. One patient each with PFIC type 1 underwent retransplantation due to graft failure or died due to multi-organ failure. Overall graft and patient survival rates at five years were 66.7% and 83.3%, respectively. Bile salt export pump immunohistochemical staining showed normal canalicular expression in two patients with PFIC type 1, focal loss in two patients with PFIC type 2, and total loss in three patients with PFIC type 2. Conclusions: LT is currently the only effective treatment for PFIC-associated end-stage liver diseases. It is mandatory to perform regular follow-up due to the risk of complications including steatohepatitis, especially for patients with PFIC type 1.

• Annals of Occupational and Environmental Medicine
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• v.34
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• pp.33.1-33.13
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• 2022

Background: Circadian rhythm disturbance caused by shift work has adverse effects on the metabolic homeostasis of the liver. Disruption of the metabolic homeostasis of the liver causes fat accumulation in the liver. The aim of this study was to investigate the correlation between shift work and non-alcoholic fatty liver disease (NAFLD) among male workers in the steel manufacturing industry of Korea. Methods: Based on medical examination data collected in June 2020, 2,511 male subjects from one steel manufacturing company in Korea were selected in total. NAFLD was evaluated using abdominal ultrasound, which was performed by two experienced radiologists. The multinomial logistic regression analysis was performed by adjusting for age, physical activity, smoking history, alcohol consumption, body mass index, waist circumference, blood pressure, blood glucose, lipidemia, liver function test, employment duration, and hepatotoxic materials exposure status. Results: Compared to daytime workers, the odds ratio (OR) of moderate-severe NAFLD in shift workers was 1.449 (95% confidence interval [CI], 1.028-2.043). Compared to daytime workers, the ORs of moderate-severe NAFLD were significantly higher for the group that engaged in total shift work for more than 20 years (OR, 2.285; 95% CI, 1.051-4.970), the group that was not allowed to sleep during night shift work (OR, 1.463; 95% CI, 1.030-2.078), and the group that consumed food during night shift work (OR, 1.580; 95% CI, 1.093-2.284). Conclusions: There was a correlation between shift work and moderate-severe NAFLD in male steel manufacturing workers. There will be a need for more research related to the correlation of shift work with steatohepatitis and cirrhosis in the future.

• 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.

• Journal of Ginseng Research
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• v.45 no.2
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• pp.316-324
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• 2021

Background: Korea Red Ginseng (KRG) has been used as remedies with hepato-protective effects in liver-related condition. Microbiota related gut-liver axis plays key roles in the pathogenesis of chronic liver disease. We evaluated the effect of KRG on gut-liver axis in patients with nonalcoholic statohepatitis by the modulation of gut-microbiota. Methods: A total of 94 patients (KRG: 45 and placebo: 49) were prospectively randomized to receive KRG (2,000 mg/day, ginsenoside Rg1+Rb1+Rg3 4.5mg/g) or placebo during 30 days. Liver function test, cytokeraton 18, and fatigue score were measured. Gut microbiota was analyzed by MiSeq systems based on 16S rRNA genes. Results: In KRG group, the mean levels (before vs. after) of aspartate aminotransferase (53 ± 19 vs. 45 ± 23 IU/L), alanine aminotransferase (75 ± 40 vs. 64 ± 39 IU/L) and fatigue score (33 ± 13 vs. 26 ± 13) were improved (p < 0.05). In placebo group, only fatigue score (34 ± 13 vs. 31 ± 15) was ameliorated (p < 0.05). The changes of phyla were not statistically significant on both groups. In KRG group, increased abundance of Lactobacillus was related with improved alanine aminotransferase level and increased abundance of Clostridium and Intestinibacter was associated with no improvement after KRG supplementation. In placebo group, increased abundance of Lachnospiraceae could be related with aggravation of liver enzyme (p < 0.05). Conclusion: KRG effectively improved liver enzymes and fatigue score by modulating gut-microbiota in patients with fatty liver disease. Further studies are needed to understand the mechanism of improvement of nonalcoholic steatohepatitis. ClnicalTrials.gov: NCT03945123 (www.ClinicalTrials.gov).

• Journal of the Korean Society of Food Science and Nutrition
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• v.35 no.5
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• pp.536-542
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• 2006

High fat diet and chronic alcohol consumption cause hyperlipidemia, steatohepatitis and in some cases, cirrhosis. But the detailed mechanisms are not known. Scutellariae Radix (SR) has been known to have hepatoprotective effects. The aim of this study was, therefore, to determine whether SR water extract (100 mg/kg) could affect immune function in mice abused by long-term alcohol consumption (feed 25% ethanol in water for 1 month, ad libitum) with high fat diet (40% fat of total calorie). Mice received either a regular diet (RD, AIN 93) or a high fat diet (HD); high fat diet group were divided into ethanol group (HED) or ethanol with SR water extract group (HEDS). Food consumption was measured daily and body weights recorded weekly throughout the experiment. Immunological parameters (Ig A, Ig E, TNF-$\alpha$, IFN-$\gamma$, IL-$1{\beta}$) were measured from the serum and the supernatant of spleen lymphocytes from the all groups. The concentration of serum Ig A, Ig E and cytokines were significantly higher in the alcohol consumed groups. Also the concentration of supernatant of spleen lymphocytes, Ig A, Ig E, cytokines were significantly higher in the ethanol consumption groups. Otherwise, HEDS group were significantly lower than HED group. These results suggest that SR water extract may improve the haptic immune function in mice fed high fat diet with alcohol.

• Clinical and Experimental Pediatrics
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• v.49 no.10
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• pp.1037-1041
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• 2006

Purpose : The prevalence of obesity and nonalcoholic steatohepatitis(NASH) was increased in adolescents. This study was performed to observe the prevalence of elevated aminotransferase levels in adolescents and to assess the correlations between aminotransferase levels and obesity related parameters(body mass index, waist circumference, hip circumference, waist to hip ratio and insulin level). Methods : We obtained weight, height, waist circumference and hip circumference from 2,417 male and 1,219 female adolescents. Mean age was $15.7{\pm}0.7$ years old. We measured fasting insulin, aspartate aminotransferase(AST) and alanine aminotransferase(ALT). Obese and overweight were defined as body mass indices(BMI) of more than the 95th, and 85th-94th percentiles, respectively, for age and sex. Results : The number of adolescents with obesity is 324(8.9 percent). 414(11.4 percent) subjects belonged to the overweight group. The average ALT level of obese, overweight and control groups were significantly different(obese : $32.1{\pm}34.3U/L$, overweight : $19.6{\pm}13.6U/L$, control : $12.7{\pm}6.7U/L$, P<0.001). The average AST level was also different according to group(obese : $27.8{\pm}16.5U/L$, overweight : $22.8{\pm}8.6U/L$, control : $20.8{\pm}8.5U/L$, P<0.001). AST and ALT were correlated with anthropometric parameters and insulin level. After multiple regression analysis, waist circumference was the significant predictive value for AST(r=0.234, P<0.001). Waist circumference, BMI and insulin levels were significant predictive values for ALT(r=0.435, P<0.001). Conclusion : The prevalence of abnormal aminotransferase was higher in the obese and overweight groups than control group. Waist circumference was useful to predict abnormal aminotransferase levels.