• Journal of Biomedical Engineering Research
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• v.4 no.1
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• pp.9-14
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• 1983

A new quantitative method was developed for separation of three interactive physiological factors (hepatic glucose balance, peripheral tissue's insulin resistivity, and insulin secretion rate) influencing glucose intolerance in diabetic mellitus using an equivalent circuit model and the intravenous glucose tolerance test (IVGTT) in six dogs and twenty two humans. The results show that the estimated model parameters of the above three factors are useful for evaluating different glucose-insulin kinetics in normal and diabetic subjects.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.5
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• pp.451-460
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• 2015

Sirtuin 1 (SIRT1) is a mammalian $NAD^+$-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-${\kappa}B$), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (${\alpha}$-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.

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

• Development and Reproduction
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• v.12 no.2
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• pp.183-194
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• 2008

A variety of stem cells has been emerging as therapeutic cells that can replace organ transplantation in human liver diseases. The present study focused on whether human eyelid adipose-derived stem cells (HAD) might differentiate into functional hepatocyte-like cells in vitro. HAD were isolated from human eyelid adipose tissue. Effect of dimethyl sulfoxide (DMSO), fibroblast growth factor (FGF)-2 and FGF-4 on the hepatic differentiation of HAD have been examined in vitro. Immunocytochemical analysis and PAS staining showed that HAD cultured in both DMSO and FGF-4 exhibited the most intense staining than HAD of the other experimental groups. These HAD expressed numerous hepatocyte-related genes. Immunoblotting analyses showed that HAD cultured in the presence of DMSO and FGF-4 secreted higher amount of human albumin than HAD cultured in other conditions. Urea analysis also demonstrated that these HAD produced higher amount of urea than any other groups of HAD. In conclusion, combined treatment of DMSO and FGF-4 could effectively induce the functional differentiation of HAD into hepatocyte-like cells.

• BMB Reports
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• v.49 no.3
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• pp.139-148
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• 2016

In the past decade, the incidence of type 2 diabetes (T2D) has rapidly increased, along with the associated cardiovascular complications. Therefore, understanding the pathophysiology underlying T2D, the associated complications and the impact of therapeutics on the T2D development has critical importance for current and future therapeutics. The prevailing feature of T2D is hyperglycemia due to excessive hepatic glucose production, insulin resistance, and insufficient secretion of insulin by the pancreas. These contribute to increased fatty acid influx into the liver and muscle causing accumulation of lipid metabolites. These lipid metabolites cause dyslipidemia and non-alcoholic fatty liver disease, which ultimately contributes to the increased cardiovascular risk in T2D. Therefore, understanding the mechanisms of hepatic insulin resistance and the specific role of liver lipids is critical in selecting and designing the most effective therapeutics for T2D and the associated co-morbidities, including dyslipidemia and cardiovascular disease. Herein, we review the effects and molecular mechanisms of conventional anti-hyperglycemic and lipid-lowering drugs on glucose and lipid metabolism.

• Journal of Microbiology and Biotechnology
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• v.12 no.5
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• pp.735-739
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• 2002

Large quantities of porcine hepatocyte aggregates with various degrees of aggregation (DA) could be obtained by controlling the suspension periods (0,9,24, and 48 h), and by entrapping the hepatocyte aggregates in model materials of encapsulation such as Ca-alginate and type-I collagen gels. The effects of DA on liver-specific functions of hepatocytes were evaluated in order to obtain optimum DA for the cell source of bioartificial liver (BAL) systems. Irregular rugged aggregates (size $75 \pm 28$ $\mu\textrm{m}$) farmed by 24 h of suspension culturing showed peak viability and hepatic functions such as ammonia removal and albumin secretion in the two types of entrapment systems, thus offering themselves as a stable cell source of a BAL system for hepatic functions and scale-up.

• Molecules and Cells
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• v.41 no.7
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• pp.639-645
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• 2018

Liver transplantation is recommended for patients with liver failure, but liver donors are limited. This necessitates the development of artificial livers, and hepatocytes are necessary to develop such artificial livers. Although induced hepatocyte-like cells are used in artificial livers, the characteristics of mouse induced hepatocyte-like cells (miHeps) reprogrammed with embryonic fibroblasts have not yet been clarified. Therefore, this study investigated the mechanisms underlying the survival, function, and death of miHeps. miHeps showed decreased cell viability, increased cytotoxicity, decreased hepatic function, and albumin and urea secretion at passage 14. Addition of necrostatin-1 (NEC-1) to miHeps inhibited necrosome formation and reactive oxygen species generation and increased cell survival. However, NEC-1 did not affect the hepatic function of miHeps. These results provide a basis for development of artificial livers using hepatocytes.

• Archives of Pharmacal Research
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• v.13 no.3
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• pp.227-232
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• 1990

A Physiologically based pharmacokinetic model was used to describe the distribition and elimination of cefriazone in the rat. To validate the practical application of the model, the effect of cffeine on the model was also examined. The model consisted of eleven compartments representing the major sites for ceftriaxone distribution including carcass which served as a residual compartment. Elimination was represented by renal and hepatic (metabolic biliary )excretion with GI secretion and re-absorption. The drug concentrations in most of the tissues were simulated using flow limited equations while brain levels were simulated using membrane limited passive diffusion distribution. The experimental data were obtained by averaging the concentration of drug in the plasma and tissues of five rats after i. v. injection of cefriazone 100 mg/kg without and with caffeine 20 mg/kg. The data for the amount of ceftriazone excreted in urine and gut contents were used to apportion total body clearance. HPLC with UV detection was used for the assay with 0.1-0.2 $\mu$g/ml sensitivity. The great majority of drug concentrations with and without caffeine show reasonably good agreements to the simulation results within 20%. The effect of caffeine on renal and hepatic clearances was apparent with 18.8% and 18.6% increase in the model values, respectively.

• Korean Journal of Food Science and Technology
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• v.51 no.1
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• pp.24-28
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• 2019

In this study, the in vitro hepatotoxic mechanism of Ephedra sinica (ma-huang) was investigated by measuring the degree of cell death, secretion of cytokine, and fat accumulation by treating HepG2 cells with 70% ethanolic extracts of ma-huang. Cell death was observed at concentrations of around $5-100{\mu}g/mL$ by treatment with ma-huang extracts (p<0.05). The secretion of interleukin 8 (IL-8) and macrophage colony-stimulating factor (M-CSF), which are inflammatory cytokines, were significantly promoted at concentrations of around 0.05-100 and $0.5-100{\mu}g/mL$, respectively (p<0.05). In this experiment, it was shown that the extracts of ma-huang stimulate the secretion of inflammatory cytokines, such as IL-8 and M-CSF, and lead to fat accumulation in the hepatocytes, thereby causing inflammation of the hepatocytes. Hepatotoxicity was observed at around 10-500 times lower concentration than the concentration required to cause serious toxicity, such as cell death, suggesting that hepatic toxicity (hepatitis) may be induced at a low dose.

• Journal of Microbiology and Biotechnology
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• v.17 no.12
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• pp.1983-1990
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• 2007

Antidiabetic effects of a novel microbial biopolymer (PGB) 1 excreted from new Enterobacter sp. BL-2 were tested in the db/db mice. The animals were divided into normal control, rosiglitazone (0.005%, wt/wt), low PGB1 (0.1%, wt/wt), and high PGB1 (0.25%, wt/wt) groups. After 5 weeks, the blood glucose levels of high PGB1 and rosiglitazone supplemented groups were significantly lower than those of the control group. In hepatic glucose metabolic enzyme activities, the glucokinase activities of PGB1 supplemented groups were significantly higher than the control group, whereas the PEPCK activities were significantly lower. The plasma insulin and hepatic glycogen levels of the low and high PGB1 supplemented groups were significantly higher compared with the control group. Specifically, the insulin and glycogen increases were dose-responsive to PGB1 supplement. PGB1 supplement did not affect the IPGTT and IPITT compared with the control group; however, rosiglitazone significantly improved IPITT. High PGB1 and rosiglitazone supplementation preserved the appearance of islets and insulin-positive cells in immunohistochemical photographs of the pancreas compared with the control group. These results demonstrated that high PGB1 (0.25% in the diet) supplementation seemingly contributes to preventing the onset and progression of type 2 diabetes by stimulating insulin secretion and enhancing the hepatic glucose metabolic enzyme activities.