• BMB Reports
• /
• v.53 no.2
• /
• pp.100-105
• /
• 2020

While liver histopathology is heterogeneous in diabetes, the underlying mechanisms remain unclear. We investigated whether glycemic variation resulting from differential diets can induce heterogeneity in diabetic liver and the underlying molecular mechanisms. We generated end-stage non-obese diabetic model rats by subtotal-pancreatectomy in male Sprague-Dawley rats and ad libitum diet for 7 weeks (n = 33). The rats were then divided into three groups, and fed a standard- or a low-protein diet (18 or 6 kcal%, respectively), for another 7 weeks: to maintain hyperglycemia, 11 rats were fed ad libitum (18AL group); to achieve euglycemia, 11 were calorie-restricted (18R group), and 11 were both calorie- and protein-restricted with the low-protein diet (6R group). Overnight-fasted liver samples were collected after the differential diets together with sham-control (18S group), and histology and molecular changes were compared. Hyperglycemic-18AL showed glycogenic hepatopathy (GH) without steatosis, with the highest GSK-3β inactivation because of Akt activation during hyperglycemia; mitochondrial function was not impaired, compared to the 18S group. Euglycemic-18R showed neither GH nor steatosis, with intermediate GSK-3β activation and mitochondrial dysfunction. However, euglycemic-6R showed both GH and steatosis despite the highest GSK-3β activity and no molecular evidence of increased lipogenesis or decreased ApoB expression, where mitochondrial dysfunction was highest among the groups. In conclusion, heterogeneous liver histopathology developed in end-stage non-obese diabetic rats as the glycemic levels varied with differential diets, in which protein content in the diets as well as glycemic levels differentially influenced GSK-3β activity and mitochondrial function in insulin-deficient state.

• Toxicological Research
• /
• v.34 no.1
• /
• pp.23-29
• /
• 2018

Ethanol-induced fat accumulation, the earliest and most common response of the liver to ethanol exposure, may be involved in the pathogenesis of liver diseases. Isoliquiritigenin (ISL), an important constituent of Glycyrrhizae Radix, is a chalcone derivative that exhibits antioxidant, anti-inflammatory, and phytoestrogenic activities. However, the effect of ISL treatment on lipid accumulation in hepatocytes and alcoholic hepatitis remains unclear. Therefore, we evaluated the effect and underlying mechanism of ISL on ethanol-induced hepatic steatosis by treating AML-12 cells with 200 mM ethanol and/or ISL ($0{\sim}50{\mu}M$) for 72 hr. Lipid accumulation was assayed by oil red O staining, and the expression of sirtuin1 (SIRT1), sterol regulatory element-binding protein-1c (SREBP-1c), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor alpha ($PPAR{\alpha}$) was studied by western blotting. Our results indicated that ISL treatment upregulated SIRT1 expression and downregulated SREBP-1c expression in ethanol-treated cells. Similarly, oil red O staining revealed a decrease in ethanol-induced fat accumulation upon co-treatment of ethanol-treated cells with 10, 20, and $50{\mu}M$ of ISL. These findings suggest that ISL can reduce ethanol induced-hepatic lipogenesis by activating the SIRT1-AMPK pathway and thus improve lipid metabolism in alcoholic fatty livers.

• The Journal of the Korea Contents Association
• /
• v.17 no.7
• /
• pp.215-221
• /
• 2017

The purpose of present study was to assess whether Gd-EOB-DTPA with gadolinium-based contrast agent administration affects fat quantification using the two-point Dixon technique. Between April 2016 and September, 60 patients who underwent hepatic fat quantification using the two-point Dixon technique were divided into two group (normal liver donors=30, abnormal hepatic steatosis=30) and we compared the variability of mean fat fraction before and after administration Gd-EOB-DTPA. As a results, in both group, fat fraction after injection Gd-EOB-DTPA was significantly decreased (normal liver donors -33.8%, hepatic steatosis -47.2%) compared to before injection Gd-EOB-DTPA, suggesting that Gd-EOB-DTPA affects fat quatification using two-point Dixon technique. In conclusion, hepatic fat quantification using the two-point Dixon technique could maintain diagnostic value by acquiring images before administration Gd-EOB-DTPA.

• Proceedings of the Korean Society of Veterinary Pathology Conference
• /
• 2002.11a
• /
• pp.132-132
• /
• 2002

Mostly, hypercholesterolemia has been focused on atherosclerosis and coronary heart disease and can be produced by intake of high cholesterol diet. However, toxic effects of cholesterol itself on liver and relationship between intake of high cholesterol diet and hepatic fibrosis have not been clearly investigated. Male Wistar rats were fed diet supplemented with 1.0 ％ cholesterol and 0.3 ％ sodium cholate for 12 weeks. Rats were sacrificed at 0, 3, 6, 9 and 12, respectively. Histopathological and blood chemical studies were performed on these animal sets. Total cholesterol, AST, ALT and LDH levels increased from week 3 and maintained around that level throughout the experiment compared to control. However, TG and albumin levels were the same or lower than those of control. Intake of high cholesterol and sodium cholate diet caused hepatic necrosis, macrophage infiltration, steatosis and fibrosis. Following feeding this diet to rats, hepatic necrosis, macrophage infiltration and steatosis markedly increased throughout the experiment, comparing to control. Collagen deposition and myofibroblasts were detected from at week 9 to 12 in the liver. Mast cell increased in proportion to the degree of hepatic damages. In conclusion, these results suggest that intake of high cholesterol diet is a risk factor on hepatic steatosis and fibrosis as well as atherosclerosis and coronary heart disease. Furthermore, this animal model for hepatic fibrosis can be use for application of anti-fibrogenic agents screening in vivo.

• The Korean Journal of Physiology and Pharmacology
• /
• v.23 no.6
• /
• pp.459-466
• /
• 2019

Dipeptidyl peptidase (DPP)-4 inhibitors, or gliptins, are a class of oral hypoglycemic drugs that have been widely used as a second-line treatment for type 2 diabetes. Gliptins, which were introduced for clinical use a decade ago, have been shown to be beneficial against nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) in animals and humans. Cenicriviroc (CVC), a dual antagonist of C-C chemokine receptor type 2 and 5, is currently under investigation against NASH and fibrosis. It was previously discovered that evogliptin (EVO) reduces hepatic steatosis in diet-induced obese animals but the effectiveness of EVO on NASH remains unexplored. Here, we compared the effectiveness of EVO and CVC against NASH and fibrosis in mice fed a high-fat and high-fructose diet (HFHF). Biochemical and histological analyses showed that mice fed a HFHF for 20 weeks developed severe hepatic steatosis and inflammation with mild fibrosis. Administration of EVO (0.2% wt/wt) for the last 8 weeks of HFHF feeding significantly reduced hepatic triglyceride accumulation, inflammation, and fibrosis as well as restored insulin sensitivity, as evidenced by lowered plasma insulin levels and the improvement in insulin tolerance test curves. Treatment of mice with CVC (0.1% wt/wt) inhibited hepatic inflammation and fibrogenesis with similar efficacy to that of EVO, without affecting hepatic steatosis. CVC treatment also reduced plasma insulin concentrations, despite no improvement in insulin tolerance. In conclusion, EVO administration efficiently ameliorated the development of NASH and fibrosis in HFHF-fed mice, corroborating its therapeutic potential.

• Korean Journal of Transplantation
• /
• v.31 no.4
• /
• pp.177-181
• /
• 2017

Living donor liver transplantation (LDLT) has become an inevitable procedure due a shortage of deceased donors under the influence of religious and native cultures. The most important concern in LDLT is donor safety. This study reviewed the safety of LDLT donors from reported studies of morbidity and mortality. Many studies have reported mortality and morbidity rates ranging from 0% to 33% for healthy liver donors. Use of laparoscopic surgery on LDLT donors has advantages of reduced blood loss, lower postoperative morbidity and shorter hospital stay relative to conventional open surgery. There is a consensus that remnant liver volume (RLV), degree of steatosis, and donor age are the most important factors influencing donor safety. In LDLT, donor hepatectomy can be performed successfully with minimal and easily controlled complications. However, a large-scale prospective cohort study is needed to better understand the risk factors and accurately determine the complication rates for LDLT.

• Journal of Korean Medicine for Obesity Research
• /
• v.24 no.1
• /
• pp.1-12
• /
• 2024

Objectives: Ephedrae herba (EH) and Coicis semen (CS) has been frequently prescribed for the treatment of obesity. However, effects of combinational extracts of these two herbs on non-alcoholic fatty liver disease are unknown. The aim of the present study was to investigate the effects of EH and CS on lipid accumulation and glucose absorption in free fatty acids (FFAs) or palmitic acid (PA)-treated HepG2 cells. Methods: Five samples of EH and CS were extracted by combination ratios (S1=0:100, S2=25:75, S3=50:50, S4=75:25, S5=100:0). Oil Red O staining was used to measure lipid accumulation in FFAs-induced steatosis cells. Intracellular triglycerides and total cholesterol levels were measured in FFAs-induced steatotic HepG2 cells. In PA-treated cells, intracellular 2-NBDG was detected using a fluorescence microplate reader and flow cytometry. Phosphorylation of key metabolism-related factors of AMP-activated protein kinase and acetyl-CoA carboxylase, expression of key lipid synthesis-related factors carnitine palmitoyltransferase 1 alpha (CPT1α), sterol regulatory element-binding protein 1 (SREBP1), peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT enhancer binding protein alpha (C/EBPα) were confirmed by western blot. Results: Treatment of EH-CS combination in the FFAs-induced steatotic HepG2 cells significantly reduced lipid accumulation. As the relative ratio of Ephedrae herba increased, the lipid-lowering effects of the combination were increased. However, S1 and S5 of Ephedrae herba and Coicis semen did not significantly reduce triglycerides and total cholesterol induced by FFAs. However, the combination of Ephedrae herba and Coicis semen restored glucose absorption in PA-induced HepG2 cells. Major makers of SREBP1, PPARγ, C/EBPα, and CPT1α expression tended to decrease with EH ratio. Conclusions: The EH-CS combination has advantages over sole EH and CS extracts in improving lipid and glucose metabolism in liver steatosis models.

• Journal of Ginseng Research
• /
• v.44 no.2
• /
• pp.238-246
• /
• 2020

Background: Dietary fat has been suggested to be the cause of various health issues. Obesity, hypertension, cardiovascular disease, diabetes, dyslipidemia, and kidney disease are known to be associated with a high-fat diet (HFD). Obesity and associated conditions, such as type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD), are currently a worldwide health problem. Few prospective pharmaceutical therapies that directly target NAFLD are available at present. A Traditional Chinese Medicine, ginseng-plus-Bai-Hu-Tang (GBHT), is widely used by diabetic patients to control glucose level or thirst. However, whether it has therapeutic effects on fat-induced hepatic steatosis and metabolic syndrome remains unclear. Methods: This study was conducted to examine the therapeutic effect of GBHT on fat-induced obesity, hepatic steatosis, and insulin resistance in mice. Results: GBHT protected mice against HFD-induced body weight gain, hyperlipidemia, and hyperglycemia compared with mice that were not treated. GBHT inhibited the expansion of adipose tissue and adipocyte hypertrophy. No ectopic fat deposition was found in the livers of HFD mice treated with GBHT. In addition, glucose intolerance and insulin sensitivity in HFD mice was also improved by GBHT. Conclusion: GBHT prevents changes in lipid and carbohydrate metabolism in a HFD mouse model. Our findings provide evidence for the traditional use of GBHT as therapy for the management of metabolic syndrome.

• Clinical and Experimental Pediatrics
• /
• v.56 no.2
• /
• pp.45-51
• /
• 2013

Because nonalcoholic steatohepatitis can progress towards cirrhosis even in children, early detection of hepatic fibrosis and accurate diagnosis of nonalcoholic fatty liver disease (NAFLD) are important. Although liver biopsy is regarded as the gold standard of diagnosis, its clinical application is somewhat limited in children due to its invasiveness. Noninvasive diagnostic methods, including imaging studies, biomarkers of inflammation, oxidative stress, hepatic apoptosis, hepatic fibrosis, and noninvasive hepatic fibrosis scores have recently been developed for diagnosing the spectrum of NAFLD, particularly the severity of hepatic fibrosis. Although data and validation are still lacking for these noninvasive modalities in the pediatric population, these methods may be applicable for pediatric NAFLD. Therefore, noninvasive imaging studies, biomarkers, and hepatic fibrosis scoring systems may be useful in the detection of hepatic steatosis and the prediction of hepatic fibrosis, even in children with NAFLD.

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