• Journal of Microbiology and Biotechnology
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• v.31 no.2
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• pp.181-188
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• 2021

Bacillus subtilis and Enterococcus faecium are commonly used probiotics. This study aimed to identify the effect of live combined Bacillus subtilis R0179 and Enterococcus faecium R0026 (LCBE) on obesity-associated hyperlipidemia and gut microbiota in C57BL/6 mice. Forty male C57BL/6 mice were divided into four groups: normal group (N group), model group (M group), low-dose group (L group), and high-dose group (H group). Mice were gavaged with LCBE at 0.023 g/mice/day (L group) or 0.23 g/mice/day (H group) and fed with a high-fat diet for 8 weeks. In vitro E. faecium R0026 showed an ability to lower the low-concentration of cholesterol by 46%, and the ability to lower the high-concentration of cholesterol by 58%. LCBE significantly reduced the body weight gain, Lee index, brown fat index and body mass index of mice on a high-fat diet. Moreover, LCBE markedly improved serum lipids (including serum triglyceride, total cholesterol, low-density lipoprotein and high-density lipoprotein) while also significantly reducing liver total cholesterol. Serum lipopolysaccharide and total bile acid in L and H groups decreased significantly compared with M group. PCR-DGGE analysis showed that the composition of gut microbiota in the treatment groups was improved. Akkermansia muciniphila was found in H group. The PCA result indicated a similar gut microbiota structure between LCBE treatment groups and normal group while the number of bands and Shannon diversity index increased significantly in the LCBE treatment groups. Finally, qPCR showed Bifidobacterium spp. increased significantly in H group compared with M group, LCBE alleviated liver steatosis and improved brown adipose tissue index.

• Biomolecules & Therapeutics
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• v.32 no.1
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• pp.94-103
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• 2024

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of fat in the liver, and there is a global increase in its incidence owing to changes in lifestyle and diet. Recent findings suggest that p53 is involved in the development of non-alcoholic fatty liver disease; however, the association between p53 expression and the disease remains unclear. Doxorubicin, an anticancer agent, increases the expression of p53. Therefore, this study aimed to investigate the role of doxorubicin-induced p53 upregulation in free fatty acid (FFA)-induced intracellular lipid accumulation. HepG2 cells were pretreated with 0.5 ㎍/mL of doxorubicin for 12 h, followed by treatment with FFA (0.5 mM) for 24 h to induce steatosis. Doxorubicin pretreatment upregulated p53 expression and downregulated the expression of endoplasmic reticulum stress- and lipid synthesis-associated genes in the FFA -treated HepG2 cells. Additionally, doxorubicin treatment upregulated the expression of AMP-activated protein kinase, a key modulator of lipid metabolism. Notably, siRNA-targeted p53 knockdown reversed the effects of doxorubicin in HepG2 cells. Moreover, doxorubicin treatment suppressed FFA -induced lipid accumulation in HepG2 spheroids. Conclusively, these results suggest that doxorubicin possesses potential application for the regulation of lipid metabolism by enhance the expression of p53 an in vitro NAFLD model.

• The Journal of Internal Korean Medicine
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• v.35 no.2
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• pp.175-183
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• 2014

Objectives : We tried to uncover the anti-lipogenic effect and underlying mechanism of Laminaria japonica on an experimental cellular model of non-alcoholic fatty liver disease. Methods : Ethanol extract of Laminaria japonica (LJ) was prepared. Intracellular lipid content of palmitate-treated HepG2 cells was evaluated with or without LJ treatment. We measured the effects of LJ on liver X receptor ${\alpha}$ ($LXR{\alpha}$) and sterol regulatory element-binding transcription factor-1c (SREBP-1c) expression, transcription level of lipogenic genes, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD-1), and nuclear factor erythroid 2-related factor 2 (Nrf2) activation in HepG2 cells. Results : LJ markedly attenuated palmitate-induced intracellular lipid accumulation in HepG2 cells. LJ suppressed $LXR{\alpha}$-dependent SREBP-1c activation, and SREBP-1c mediated induction of ACC, FAS, and SCD-1. Furthermore, LJ activated Nrf2, which plays an important cytoprotective role in non-alcoholic fatty liver disease. Conclusions : Our study suggests that LJ has the potential to alleviate hepatic lipid accumulation, and this effect was mediated by inhibiting the $LXR{\alpha}$-SREBP-1c pathway that leads to hepatic steatosis. In addition, the anti-lipogenic potential may, at least in part, be associated with activation of Nrf2.

• Journal of Physiology & Pathology in Korean Medicine
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• v.27 no.6
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• pp.802-808
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• 2013

Here we tried to uncover the potential anti-lipogenic effect and the underlying mechanism of Phaseolus angularis seed in a cellular model of nonalcoholic fatty liver disease (NAFLD) induced in HepG2 cells. Ethanol extract of Phaseolus angularis seed (JSD) was prepared. HepG2 cells were incubated in palmitate containing media to induce intracellular lipid accumulation, and co-treated with JSD for 16 hrs before examine intracellular lipid content. In control group, the cells were not co-treated with JSD. We measured the effects of JSD on liver X receptor ${\alpha}$ ($LXR{\alpha}$) and sterol regulatory element-binding transcription factor-1c (SREBP-1c) expression, transcription level of lipogenic genes, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD-1), and AMP-activated protein kinase (AMPK) activation in HepG2 cells. JSD markedly reduced palmitate-induced intracellular lipid accumulation in HepG2 cells. JSD suppressed $LXR{\alpha}$/SREBP-1c expression, and SREBP-1c mediated induction of ACC, FAS, and SCD-1. Furthermore, JSD activated AMPK, which plays a major role in the control of hepatic lipid metabolism. Taken together, it is suggested that JSD has a potential to alleviate hepatic steatosis, at least in part, by suppressing $LXR{\alpha}$/SREBP-1c mediated induction of lipogenic genes. In addtion, the anti-lipogenic potential may be associated with activation of AMPK. Therefore, the Phaseolus angularis seed could be applied as a potential therapeutics for NAFLD with additional clinical studies.

• Journal of the Korean Society of Food Science and Nutrition
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• v.42 no.10
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• pp.1576-1584
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• 2013

This study is carried out to assess the relative effects of different doses of dietary glucose or fructose on non-alcoholic fatty liver disease (NAFLD) and hepatic metaflammation in a rodent model of type 2 diabetes. KK/HlJ male mice were fed experimental diets as follows: 1) control (CON), 2) moderate glucose (MG, 30% of total calories as glucose), 3) high glucose (HG, 60% of total calories as glucose), 4) moderate fructose (MF, 30% of total calories as fructose), and 5) high fructose (HF, 60% of total calories as fructose) for three weeks. Food intake was not affected by treatments. Compared with HF, HG not only increased serum fasting glucose and area under the curve during oral glucose tolerance test, but also decreased the levels of serum insulin and adiponectin. It indicated that glucose control was complicated via high glucose intake. High fructose treatment led to increased triglyceride in the serum and liver. In comparison to HG, high fructose diet activated NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome consisting of apoptosis-associated speck-like protein containing a CARD (ASC), NLRP3 and caspase 1, which increases interleukin (IL)-$1{\beta}$ maturation and secretion. The activation of NLRP3 inflammasome was accompanied by increased levels of tumor necrosis factor alpha (TNF-${\alpha}$) and IL-6. However, the expression of NLRP3 inflammasome components and pro-inflammatory cytokines did not differ between CON and HG. These data suggested that dietary fructose triggers hepatic metaflammation accompanied by NLRP3 inflammasome activation and has deleterious effects on NAFLD.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.6
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• pp.449-454
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• 2009

5'-AMP-activated protein kinase (AMPK) is a heterotrimeric complex consisting of a catalytic ($\alpha$) and two regulatory ($\beta$ and $\gamma$) subunits. Two isoforms are known for catalytic subunit (${\alpha}1$, ${\alpha}2$) and are encoded by different genes. To assess the metabolic effects of $AMPK{\alpha}1$, we examined the effects of overexpression of adenoviral-mediated $AMPK{\alpha}1$ in hyperlipidemic type 2 diabetic rats. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an established animal model of type 2 diabetes that exhibits chronic and slowly progressive hyperglycemia and hyperlipidemia. Thirty five-week-old overt type 2 diabetic rats (n=10) were administered intravenously with Ad.$AMPK{\alpha}1$. AMPK activity was measured by phosphorylation of acetyl CoA carboxlyase (ACC). To investigate the changes of gene expression related glucose and lipid metabolism, quantitative real-time PCR was performed with liver tissues. Overexpression of $AMPK{\alpha}1$ showed that blood glucose concentration was decreased but that glucose tolerance was not completely recovered on 7th day after treatment. Plasma triglyceride concentration was decreased slightly, and hepatic triglyceride content was markedly reduced by decreasing expression of hepatic lipogenic genes. Overexpression of $AMPK{\alpha}1$ markedly improved hepatic steatosis and it may have effective role for improving hepatic lipid metabolism in hyperlipidemic state.

• Clinical and Experimental Pediatrics
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• v.62 no.12
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• pp.450-455
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• 2019

Background: Lipid accumulation product (LAP) is associated with the presence and severity of nonalcoholic fatty liver disease (NAFLD) in adults. Purpose: Here we evaluated the ability of LAP to predict NAFLD in obese children. Methods: Eighty obese children (38 girls; age 6-18 years) were included. Anthropometric measurements and biochemical values were obtained from the patients' medical records. LAP was calculated as [waist circumference (WC) (cm) - 58]×triglycerides (mmol/L) in girls; [WC (cm) - 65]×triglycerides (mmol/L) in boys. The minLAP and adjLAP were described (3% and 50% of WC values, respectively) and the total/high-density lipoprotein cholesterol index (TC/HDL-C) was calculated. NAFLD was observed on ultrasound, and patients were divided into 3 groups by steatosis grade (normal, grade 0; mild, grade 1; moderate-severe, grade 2-3). The area under the curve (AUC) and appropriate index cutoff points were calculated by receiver operator characteristic analysis. Results: LAP was positively correlated with puberty stage (rho=0.409; P<0.001), fasting insulin (rho= 0.507; P<0.001), homeostasis model assessment of insulin resistance (rho=0.470; P<0.001), uric acid (rho=0.522; P<0.001), and TC/HDL-C (rho=0.494; P<0.001) and negatively correlated with HDL-C (rho=-3.833; P<0.001). LAP values could be used to diagnose hepatosteatosis (AUC=0.698; P=0.002). The LAP, adjLAP, and minLAP cutoff values were 42.7 (P=0.002), 40.05 (P=0.003), and 53.47 (P= 0.08), respectively. For LAP, the differences between the normal and mild groups (P=0.035) and the normal and moderate-severe groups were statistically significant (P=0.037), whereas the difference between the mild and moderate-severe groups was not (P>0.005). There was a statistically significant difference between the normal and mild groups for adjLAP (P=0.043) but not between the other groups (P>0.005). There was no significant intergroup difference in minLAP (P>0.005). Conclusion: LAP is a powerful and easy tool to predict NAFLD in childhood. If LAP is ≥42.7, NAFLD should be suspected. This is the first study to assess LAP diagnostic accuracy for childhood obesity.

• Laboraroty Animal Research
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• v.34 no.4
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• pp.288-294
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• 2018

A few clues about correlation between endoplasmic reticulum (ER) stress and mulberry (Morus alba) leaves were investigated in only the experimental autoimmune myocarditis and streptozotocin-induced diabetes. To investigate whether a novel extract of mulberry leaves fermented with Cordyceps militaris (EMfC) could suppress ER in fatty liver, alterations in the key parameters for ER stress response were measured in high fat diet (HFD)-induced obese C57L/6 mice treated with EMfC for 12 weeks. The area of adipocytes in the liver section were significantly decreased in the HFD+EMfC treated group as compared to the HFD+Vehicle treated group, while their level was higher in HFD+Vehicle treated group than No treated group. The level of the eukaryotic initiation factor 2 alpha ($eIF2{\alpha}$) and inositol-requiring enzyme 1 beta ($IRE1{\alpha}$) phosphorylation and CCAAT-enhancer-binding protein homologous protein (CHOP) expression were remarkably enhanced in the HFD+Vehicle treated group. However, their levels were restored in the HFD+EMfC treated group, although some differences were detected in the decrease rate. Similar recovery was observed on the ER stress-induced apoptosis. The level of Caspase-3, Bcl-2 and Bax were decreased in the HFD+EMfC and HFD+orlistat (OT) treated group compared to the HFD+Vehicle treated group. The results of the present study therefore provide first evidence that EMfC with the anti-obesity effects can be suppressed ER stress and ER stress-induced apoptosis in the hepatic steatosis of HFD-induced obesity model.

• Food Engineering Progress
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• v.21 no.4
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• pp.318-325
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• 2017

Alcoholic steatosis is a fundamental metabolic disorder and may precede the onset of more severe forms of alcoholic liver disease. In this study, we isolated enzymatichydrolysate from Semisulcospira libertine by alcalase hydrolysis and investigated the protective effect of Semisulcospira libertine hydrolysate on liver injury induced by alcohol in the mouse model of chronic and binge ethanol feeding (NIAAA). In an in vitro study, the hydrolysate protects HepG2 cells from ethanol toxicity. Liver damage was assessed by histopathological examination, as well as by quantitating activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). After the administration of S. libertina hydrolysate, fat accumulation and infiltration of inflammatory cells in liver tissues were significantly decreased in the NIAAA mouse model. The elevated levels of serum AST, ALT, and ALP activities, along with the lipid contents of a damaged liver, were recovered in experimental mice administrated with S. libertina hydrolysate, suggesting its role in blood enzyme activation and lipid content restoration within damaged liver tissues. Moreover, treatment with S. libertine hydrolysate reduced the expression rate of cyclooxygenase (COX-2), interleukin $(IL)-1{\beta}$, and IL-6, which accelerate inflammation and induces tissue damage. All data showed that S. libertine hydrolysate has a preventive role against alcohol-induced liver damages by improving the activities of blood enzymes and modulating the expression of inflammation factor, suggesting S. libertine hydrolysate could be a commercially potential material for the restoration of hepatotoxicity.