• 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.

• 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.

• Clinical and Experimental Pediatrics
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• v.50 no.10
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• pp.987-994
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• 2007

Purpose : This study investigated the clinical significance of AN in children and adolescents with obesity induced metabolic complications. Methods : Forty-nine patients who had obesity induced metabolic complications were participated in this cross-sectional study. Obesity induced metabolic complications are as follows: hypertension, dyslipidemia, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), nonalcoholic steatohepatitis (NASH), homeostasis model assessment of insulin resistance (HOMA-IR)>3.16. Clinical characteristics, such as, age, percentage-weight-for-height (PWH), pubertal status, blood pressure (BP), fasting plasma insulin level, fasting and post-oral glucose tolerance test 2-hour glucose levels, liver function test, lipid profile, HOMA-IR were compared according to the presence of AN. Results : Sixty-five percent of patients had AN, 57.1% NASH, 57.1% dyslipidemia, 55.1% hypertension, 46.9% IFG, 24.5% HOMA-IR>3.16 and 16.2% IGT. The patients who were moderately to severely obese with AN had higher incidence of IGT and HOMA-IR>3.16. The patients with AN had significantly higher diastolic BP ($79.4{\pm}6.9$ vs $75.4{\pm}5.6mmHg$), fasting levels of plasma insulin ($10.6{\pm}6.0$ vs $6.2{\pm}5.4{\mu}IU/mL$), HOMA-IR index ($2.6{\pm}1.4$ vs $1.4{\pm}1.3$) and PWH ($42.4{\pm}13.0$ vs $34.3{\pm}1.8%$). The increasing tendency for the presence of AN was significantly related to the cumulative number of obesity induced metabolic complications. Binary logistic regression analysis revealed that the presence of AN was significantly associated with fasting plasma insulin level, PWH and IFG. Conclusion : AN could be useful as a clinical surrogate of obesity induced metabolic complications.

• 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.

• Journal of Veterinary Clinics
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• v.27 no.4
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• pp.348-365
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• 2010

Artemisia capillaries THUNB is a perennial herb that belongs to the family compositae spp. and the most common plant among the various herbal folk remedies used in treatment of abdominal pain, hepatitis, chronic liver disease, jaundice and coughing in Korea. The object of this study is to observe the dosage-dependent anti-obestic effects of an aqueous extracts of dried aqueous extracts of stems of Artemisia capillaris Thunberg. [Artemisiae capillaris Herba, In-Jin in Korean, INJ] on 45%/Kcal high fat diet (HFD) supplied mice. 45%/Kcal rodent HFD are supplied to ICR mice from 1 week before initiation of INJ administration throughout the 12 weeks, and after the end of 12 weeks of 62.5, 125 and 250 mg/kg/day of INJ administration, the efficacy was divided into five categories 1) hypoglycemic, 2) hepato-protective, 3) nephroprotective, 4) hypolipemic, and 5) anti- obesity effects. The effects were compared to those of simvastatin (for hypolipemic activity), silymarin (for hepatoprotective and free radical scavenger effects) and metformin (for hypoglycemic and related anti-obesity effects). 7 animals per group (8 groups; total 56adapted mice on HFD were selected base on the body weight at 6 days after initiation of HFD supply) were used in this experiment. INJ and all three different reference drugs were directly suspended or dissolved in distilled water, and administered at a volume of 10 mL/kg, once a day for 84 days from 1 week after HFD supply. As results of 91 days of continuous HFD supply, mice showed marked obese states, hyperglycemia, hyperlipemia, liver damages and kidney damages. These mean the obesity, diabetes, diabetic hepatopathies, nephropathies and hyperlipemia were induced by HFD supply. After end of 84 days of continuous treatment of three different dosages of INJ, all diabetes related complications were inhibited; relatively favorable anti-obesity, hypolipemic, hepatoprotective, hypoglycemic and nephroprotective effects. These favorable effects showed relatively good dose-relations between all three different dosages of INJ treated, and INJ 250 mg/kg showed enough favorable effects on diabetes and related four complications tested as compared with one of each three different references. Otherwise, the efficacy of 62.5 and 125 mg/kg of INJ was somewhat slighter than those of all three reference drugs. Therefore, the suitable effective dosage of INJ is considered as 250 mg/kg/day in the present study. The overall anti-obesity effects of INJ 250 mg/kg-treated group was similar or more favorable than those of metformin 250 mg/kg-treated group, and INJ 250 mg/kg showed slighter hypoglycemic effects with silymarin 100 mg/kg and metformin 250 mg/kg, similar hypolipemic effects with simvastatin 10 mg/kg, and similar hepatoprotective effects with silymarin 100 mg/kg, and similar nephroprotective effects with that of silymarin 100 mg/kg and metformin 250 mg/kg, respectively. Obese, hyperglycemia, hyperlipemia, steatohepatitis and related nephropathies induced by HFD supply were dramatically inhibited by 84 days of continuous treatment of all three different dosages of INJ. It is, therefore expected that INJ extracts will be a favorable alternative agent for diet-related diabetes and complications.