• Journal of Ginseng Research
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• 제39권2호
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• pp.105-115
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• 2015

Background: Alcoholic steatosis is the earliest and most common liver disease, and may precede the onset of more severe forms of liver injury. Methods: The effect of Korean Red Ginseng extract (RGE) was tested in two murine models of ethanol (EtOH)-feeding and EtOH-treated hepatocytes. Results: Blood biochemistry analysis demonstrated that RGE treatment improved liver function. Histopathology and measurement of hepatic triglyceride content verified the ability of RGE to inhibit fat accumulation. Consistent with this, RGE administration downregulated hepatic lipogenic gene induction and restored hepatic lipolytic gene repression by EtOH. The role of oxidative stress in the pathogenesis of alcoholic liver diseases is well established. Treatment with RGE attenuated EtOH-induced cytochrome P450 2E1, 4-hydroxynonenal, and nitrotyrosine levels. Alcohol consumption also decreased phosphorylation of adenosine monophosphate-activated protein kinase, which was restored by RGE. Moreover, RGE markedly inhibited fat accumulation in EtOH-treated hepatocytes, which correlated with a decrease in sterol regulatory element-binding protein-1 and a commensurate increase in sirtuin 1 and peroxisome proliferator-activated receptor-a expression. Interestingly, the ginsenosides Rb2 and Rd, but not Rb1, significantly inhibited fat accumulation in hepatocytes. Conclusion: These results demonstrate that RGE and its ginsenoside components inhibit alcoholic steatosis and liver injury by adenosine monophosphate-activated protein kinase/sirtuin 1 activation both in vivo and in vitro, suggesting that RGE may have a potential to treat alcoholic liver disease.

• Natural Product Sciences
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• 제27권3호
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• pp.201-207
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• 2021

We have previously reported that Acer tegmentosum extract, which is traditionally used in Korea to reduce alcohol-related liver injury, suppresses liver inflammation caused by excessive alcohol consumption and might improve metabolism. The active ingredient, 6-O-galloylsalidroside (GAL), was isolated from A. tegmentosum, and we hypothesized that GAL could provide desirable pharmacological benefits by ameliorating physiological conditions caused by alcohol abuse. Therefore, this study focused on whether GAL could ameliorate alcoholic fat accumulation and repair liver injury in mice. During chronic alcohol consumption plus binge feeding in mice, GAL was administered orally once per day for 11 days. Intrahepatic lipid accumulation was measured in vivo using a noninvasive method, ¹H magnetic resonance imaging, and confirmed by staining with hematoxylin and eosin and Oil Red O. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured using a Konelab system, and the triglyceride content was measured in liver homogenates using an enzymatic peroxide assay. The results suggested that GAL alleviated alcohol-induced steatosis,e as indicated by decreased hepatic and serum triglyceride levels in ethanol-fed mice. GAL treatment also correlated with a decrease in the Cd36 mRNA expression, thus potentially inhibiting the development of alcoholic steatosis via the hepatic de novo lipogenesis pathway. Furthermore, treatment with GAL inhibited the expression of cytochrome P450 2E1 and attenuated hepatocellular damage, as reflected by a reduction in ALT and AST levels. These findings suggest that GAL extracted from A. tegmentosum has the potential to serve as a bioactive agent for the treatment of alcoholic fatty liver and liver damage.

• Nutrition Research and Practice
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• 제14권4호
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• pp.309-321
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• 2020

BACKGROUND/OBJECTIVES: The present study aimed to evaluate the effects of folic acid supplementation in high-fructose-induced hepatic steatosis and clarify the underlying mechanism of folic acid supplementation. MATERIALS/METHODS: Male SD rats were fed control, 64% high-fructose diet, or 64% high-fructose diet with folic acid for eight weeks. Plasma glutamate-pyruvate transaminase, glutamate-oxaloacetate transaminase, lipid profiles, hepatic lipid content, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) were measured. RESULTS: The HF diet significantly increased hepatic total lipid and triglyceride (TG) and decreased hepatic SAM, SAH, and SAM:SAH ratio. In rats fed a high fructose diet, folic acid supplementation significantly reduced hepatic TG, increased hepatic SAM, and alleviated hepatic steatosis. Moreover, folic acid supplementation in rats fed high fructose enhanced the levels of phosphorylated AMP-activated protein kinase (AMPK) and liver kinase B (LKB1) and inhibited phosphorylation of acetyl coenzyme A carboxylase (ACC) in the liver. CONCLUSIONS: These results suggest that the protective effect of folic acid supplementation in rats fed high fructose may include the activation of LKB1/AMPK/ACC and increased SAM in the liver, which inhibit hepatic lipogenesis, thus ameliorating hepatic steatosis. The present study may provide evidence for the beneficial effects of folic acid supplementation in the treatment of non-alcoholic fatty liver disease.

• IMMUNE NETWORK
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• 제10권6호
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• pp.181-187
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• 2010

Excessive alcohol consumption is one of the critical causative factors leading to alcoholic liver disease (ALD). ALD is characterized by a wide spectrum of liver damage, ranging from simple uncomplicated liver steatosis (fatty liver) to steatohepatitis and liver fibrosis/cirrhosis. It has been believed that the obvious underlying cause for ALD is due to hepatocyte death induced by alcohol itself. However, recent sparkling studies have shown that diverse immune responses contribute to ALD because liver is enriched with numerous immune cells. Especially, a line of evidence has suggested that innate immune cells such as Kupffer cells and natural killer (NK)/NKT cells are significantly involved in the pathogenesis of ALD via production of pro-inflammatory cytokines and other mediators. Indeed, more interestingly, hepatic stellate cells (HSCs), known as a major cell inducing liver steatosis and fibrosis, can be killed by liver NK cells, which could be suppressed by chronic alcohol consumption. In this review, with the view of liver as predominant innate immune organ, we describe the pathogenesis of ALD in which what roles of innate immune cells are and how they are interacting with HSCs.

• 대한간학회지
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• 제24권4호
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• pp.392-401
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• 2018

Background/Aims: Leptin is associated with metabolic disorders, which predispose one to non-alcoholic fatty liver disease (NAFLD). The role of leptin in NAFLD pathogenesis is not fully understood. We aim to investigate the association between serum leptin level and severity of NAFLD using U.S. nationally representative data. Methods: Data were obtained from the United States Third National Health and Nutrition Examination Survey. NAFLD was defined by ultrasound detection and severity of hepatic steatosis in the absence of other liver diseases. The severity of hepatic fibrosis was determined by NAFLD fibrosis score (NFS). We used multivariate survey-weighted generalized logistic regression to evaluate the association between leptin level and the degree of NAFLD. We also performed subgroup analyses by body mass index (lean vs. classic NAFLD). Results: Among 4,571 people, 1,610 (35%) had NAFLD. By ultrasound findings, there were 621 people with mild, 664 with moderate, and 325 with severe steatosis. There were 885 people with low NFS (<-1.455, no significant fibrosis), 596 with intermediate NFS, and 129 with high NFS (>0.676, advanced fibrosis). Leptin levels for normal, mild, moderate and severe steatosis were $10.7{\pm}0.3ng/mL$, $12.1{\pm}0.7ng/mL$, $15.6{\pm}0.8ng/mL$, $16{\pm}1.0ng/mL$, respectively (trend P-value<0.001). Leptin levels for low, intermediate, and high NFS were $11.8{\pm}0.5ng/mL$, $15.6{\pm}0.8ng/mL$, $28.5{\pm}3.5ng/mL$, respectively (trend P-value<0.001). This association remained significant even after adjusting for known demographic and metabolic risk factors. In the subgroup analysis, this association was only prominent in classic NAFLD, but not in lean NAFLD. Conclusions: Serum leptin level is associated with the severity of NAFLD, especially in classic NAFLD patients.

• Archives of Pharmacal Research
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• 제29권9호
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• pp.768-776
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• 2006

Non-alcoholic fatty liver disease (NAFLD) is common in obesity. However, weight reduction alone does not prevent the progression of NAFLD to end-stage disease associated with the development of cirrhosis and liver disease. In a previous experiment, 50% ethanol extract of Acanthopanax senticosus stem bark (ASSB) was found to reduce body weight and insulin resistance in high fat diet-induced hyperglycemic and hyperlipidemic ICR mice. To evaluate the anti-steatosis action of ASSB, insulin-resistant ob/ob mice with fatty livers were treated with ASSB ethanol extract for an 8 week-period. ASSB ethanol extract reversed the hepatomegaly, as evident in reduction of % liver weight/body weight ratio. ASSB ethanol extract also specifically lowered circulating glucose and lipids, and enhanced insulin action in the liver. These changes culminated in inhibition of triglyceride synthesis in non-adipose tissues including liver and skeletal muscle. Gene expression studies confirmed reductions in glucose 6-phosphatase and lipogenic enzymes in the liver. These results demonstrate that ASSB ethanol extract is an effective treatment for insulin resistance and hepatic steatosis in ob/ob mice by decreasing hepatic lipid synthesis.

• Toxicological Research
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• 제34권1호
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• pp.23-29
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• 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.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• 제10권2호
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• pp.185-192
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• 2007

목 적: 본 연구에서는 소아 비만 환자에서 발생하는 비알코올성 지방간 질환의 발병에 TNF-${\alpha}$, adiponectin, leptin 등의 adipokine들이 미치는 영향을 알아보며, 이들 adipokine과 체지방분포 및 인슐린 저항성과의 연관성을 함께 살펴보고자 하였다. 방 법: 2004년 3월에서 2005년 6월까지 분당서울대병원 소아과에 내원한 비만한 소아 61명을 대상으로 하여 비알코올성 지방간 질환의 상태에 따라 대상 환자들을 지방간 질환이 없는 소아 비만 환자(n=23), 단순 지방간(n=20), 그리고 비알코올성 지방간염(n=18)의 세군으로 나누고, 각 환자에서 혈중 TNF-${\alpha}$, leptin, adiponectin 농도를 측정하고 인슐린 저항성의 지표로서 HOMA-IR을 계산하였으며 복부 전산화단층촬영에서 VSR (visceral-subcutaneous fat ratio)을 산출하였다. 결 과: 총 61명(남 : 여=42 : 19, 평균 연령 11.2${\pm}$1.3세)의 환아를 대상으로 지방간 질환에 따라 세 군으로 나누었을 때, 세 군 간의 성별, 연령별 차이는 없었다(p=0.422, p=0.119). 각 군의 혈중 TNF-${\alpha}$ 농도는 유의한 차이가 없었고(22.13${\pm}$6.37 vs. 21.35${\pm}$6.95 vs. 25.17${\pm}$9.30; p=0.342), leptin 농도에도 유의한 차이가 없었으나 (20.29${\pm}$8.57 vs. 16.42${\pm}$6.85 vs. 20.10${\pm}$7.86; p=0.330), adiponectin은 유의한 차이를 보여 비알코올성 지방간염에서 혈중농도가 의미 있게 감소하였다 (6.08${\pm}$1.38 vs. 5.69${\pm}$0.79 vs. 4.93${\pm}$1.75; p=0.026). 복부 전산화단층 촬영에서 산출한 VSR도 지방간염군에서 유의하게 증가된 소견을 보였다(0.31${\pm}$0.08 vs. 0.32${\pm}$0.11 vs. 0.47${\pm}$0.14; p=0.001). HOMA-IR도 세 군에서 유의한 차이를 보였다(4.77${\pm}$3.67 vs. 6.89${\pm}$7.05 vs. 10.42${\pm}$6.73; p=0.000). 그러나 adiponectin과 HOMA-IR 또는 VSR간에 유의한 상관관계는 보이지 않았다(r=-0.117; p=0.450 & r=-0.106; p=0.499). 결 론: 인슐린 저항성은 비만한 소아에서 간 내 지방 축적과 지방간염으로의 진행과정에 모두 영향을 미칠 것으로 추정되며, 비만한 소아의 지방조직에서 분비되는 adipokine 중에서 adiponectin이 단순지방간에서 지방간염으로의 이행하는 기전에 관여할 것으로 여겨진다.

• 대한한의학회지
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• 제41권4호
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• pp.64-71
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• 2020

Objectives: This study was done to look into whether Nrf2 take some role in the anti-lipogenic effect of kaurenoic acid in a nonalcoholic fatty liver disease (NAFLD) cellular model. Materials and Methods: We measured the effect of kaurenoic acid on intracellular steatosis and Nrf2 activation. Next, the effect of kaurenoic acid on SREBP-1c and some lipogenic genes in palmitate treated HepG2 cells with or without Nrf2 silencing. Results: The increased SREBP-1c expression was significantly decreased by concomitant kaurenoic acid treatment in non-targeting negative control siRNA transfected HepG2 cells. However, kaurenoic acid did not significantly inhibited increased SREBP-1c level in Nrf2 specific siRNA transfected HepG2 cells Conclusions: Kaurenoic acid has a potential to activate Nrf2, which may suppress SREBP-1c mediated intracellular steatosis in HepG2 cells.

• 한국미생물·생명공학회지
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• 제50권1호
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• pp.157-163
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• 2022

Alcoholic liver disease (ALD), which encompasses alcoholic steatosis, alcoholic hepatitis, and alcoholic cirrhosis, is a major cause of morbidity and mortality worldwide. Although the economic and health impacts of ALD are clear, few advances have been made in its prevention or treatment. We recently demonstrated that the insect-derived antimicrobial peptide CopA3 exerts anti-apoptotic and anti-inflammatory activities in various cell systems, including neuronal cells and colonic epithelial cells. Here, we tested whether CopA3 inhibits ethanol-induced liver injury in mice. Mice were intraperitoneally injected with ethanol only or ethanol plus CopA3 for 24 h and then liver injury and inflammatory responses were measured. Ethanol enhanced the production of proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon (IFN)-γ, and IL-10. It also induced hepatocyte apoptosis and ballooning degeneration in hepatocytes. Notably, all these effects were eliminated or significantly reduced by CopA3 treatment. Collectively, our findings demonstrate that CopA3 ameliorates ethanol-induced liver cell damage and inflammation, suggesting the therapeutic potential of CopA3 for treating ethanol-induced liver injury.