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ABSTRACT: Sulforaphane (SFN) is a dietary isothiocyanate that exerts chemopreventive effects via NF-E2-related factor 2 (Nrf2)-mediated induction of antioxidant/phase II enzymes, such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). This work was undertaken to evaluate the effects of SFN on hepatic fibrosis and profibrotic transforming growth factor (TGF)-β/Smad signaling, which are closely associated with oxidative stress. SFN suppressed TGF-β-enhanced expression of α-smooth muscle actin (α-SMA), a marker of hepatic stellate cell (HSC) activation, and profibrogenic genes such as type I collagen, fibronectin, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and plasminogen activator inhibitor (PAI)-1 in hTERT, an immortalized human HSC line. SFN inhibited TGF-β-stimulated activity of a PAI-1 promoter construct and (CAGA)(9) MLP-Luc, an artificial Smad3/4-specific reporter, in addition to reducing phosphorylation and nuclear translocation of Smad3. Nrf2 overexpression was sufficient to inhibit the TGF-β/Smad signaling and PAI-1 expression. Conversely, knockdown of Nrf2, but not inhibition of HO-1 or NQO1 activity, significantly abolished the inhibitory effect of SFN on (CAGA)(9) MLP-Luc activity. However, inhibition of NQO1 activity reversed repression of TGF-β-stimulated expression of type I collagen by SFN, suggesting the involvement of antioxidant activity of SFN in the suppression of Smad-independent fibrogenic gene expression. Finally, SFN treatment attenuated the development and progression of early stage hepatic fibrosis induced by bile duct ligation in mice, accompanied by reduced expression of type I collagen and α-SMA. Collectively, these results show that SFN elicits an antifibrotic effect on hepatic fibrosis through Nrf2-mediated inhibition of the TGF-β/Smad signaling and subsequent suppression of HSC activation and fibrogenic gene expression.
Free radical biology & medicine 12/2011; 52(3):671-82. · 5.42 Impact Factor
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ABSTRACT: Non-alcoholic steatohepatitis (NASH) is a liver disease that causes fat accumulation, inflammation and fibrosis. Increased oxidative stress contributes to hepatic inflammation and fibrosis by upregulation of Cytochrome P450 2E1 (CYP2E1), endoplasmic reticulum (ER) stress and mitogen-activated protein kinase (MAPK) activity. This study examined whether alpha-lipoic acid (ALA), a naturally occurring thiol antioxidant, prevents steatohepatitis through the inhibition of several pathways involved in hepatic inflammation and fibrosis.
C57BL/6 mice were fed an MCD diet with or without ALA for 4weeks. Liver sections from mice on control or MCD diets with or without ALA were stained with hematoxylin-eosin, oil red O, and anti-4-HNE antibody. The effects of ALA on methionine-choline deficient MCD-diet induced plasma AST and ALT as well as tissue TBARS were measured. The effects of ALA on CYP2E1 expression, ER stress, MAPK levels, and NF-κB activity in MCD diet-fed mice liver were measured by northern and western blot analysis.
Dietary supplementation with ALA reduced MCD diet-induced hepatic lipid accumulation, hepatic inflammation, TBARS, 4-HNE, and plasma ALT and AST levels. These effects were associated with a reduced expression of CYP2E1 and reduced ER stress and MAPK and NF-κB activity.
Taken together, the results of the present study indicate that ALA attenuates steatohepatitis through inhibition of several pathways, and provide the possibility that ALA can be used to prevent the development and progression of non-alcoholic fatty liver disease in patients who have strong risk factors for NASH.
Life sciences 12/2011; 90(5-6):200-5. · 2.56 Impact Factor
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ABSTRACT: Accumulating evidence suggests that plasminogen activator inhibitor (PAI)-1 plays an important role in the development of hepatic fibrosis via its involvement in extracellular matrix remodeling. We previously reported that alpha-lipoic acid (ALA), a naturally occurring thiol antioxidant, prevents hepatic steatosis by inhibiting the expression of sterol regulatory element binding protein-1c. The aim of the present study was to determine whether ALA prevents hepatic PAI-1 expression and fibrosis through the inhibition of multiple TGF-beta-mediated molecular mediators. We investigated whether ALA inhibited the development of hepatic fibrosis in mice following bile duct ligation (BDL), an established animal model of liver fibrosis. We found that ALA markedly inhibited BDL-induced hepatic fibrosis and PAI-1 expression. We also found that ALA attenuated TGF-beta-stimulated PAI-1 mRNA expression, and inhibited PAI-1 promoter activity in liver cells; this effect was mediated by Smads and the JNK and ERK pathways. The results of the present study indicate that ALA inhibits hepatic PAI-1 expression through inhibition of TGF-beta-mediated molecular mediators, including Smad3, AP1, and Sp1, and prevents the development of BDL-induced hepatic fibrosis. These findings suggest that ALA may have a clinical application in preventing the development and progression of hepatic fibrosis.
Biochemical and Biophysical Research Communications 02/2010; 393(3):536-41. · 2.48 Impact Factor
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Hye-Young Seo,
Mi-Kyung Kim, Ae-Kyung Min,
Hye-Soon Kim,
Seong-Yeol Ryu,
Nam-Kyeong Kim,
Kyeong Min Lee,
Han-Jong Kim,
Hueng-Sik Choi,
Ki-Up Lee,
Keun-Gyu Park,
In-Kyu Lee
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ABSTRACT: The expression of genes encoding key hepatic gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), is regulated at the transcriptional level by a network of transcription factors and cofactors, including cAMP response element-binding protein (CREB). It has been suggested that increased endoplasmic reticulum (ER) stress in the liver impairs hepatic glucose metabolism. However, the direct effect of ER stress on hepatic gluconeogenesis is still not clear. Here, we investigated whether ER stress influences hepatic gluconeogenesis and whether this process is mediated by activating transcription factor 6 (ATF6) through the inhibition of cAMP-mediated activation of CREB. A cAMP stimulant, forskolin, and 8-bromoadenosine-cAMP increased PEPCK and G6Pase mRNA expression in H4IIE rat hepatoma cells, and ER stress induced by tunicamycin or thapsigargin decreased the expression of these genes in forskolin or 8-bromoadenosine-cAMP-treated cells. In a transient transfection study, ATF6 inhibited the PEPCK and G6Pase promoters. Also, adenovirus-mediated overexpression of ATF6 in H4IIE cells decreased forskolin-stimulated PEPCK and G6Pase gene expression. Moreover, the inhibition of endogenous ATF6 expression by small interfering RNAs restored the ER stress-induced suppression of PEPCK and G6Pase gene expression. Transient transfection of ATF6 inhibited transactivation by CREB on the PEPCK and G6Pase promoters, and a gel shift assay showed that Ad-ATF6 inhibits forskolin-stimulated CREB DNA-binding activity. Finally, we found that expression of ATF6 decreased fasting-induced PEPCK, G6Pase mRNA expression, and blood glucose levels in mice. Taken together, these data extend our understanding of ER stress and the regulation of liver gluconeogenesis by ATF6.
Endocrinology 12/2009; 151(2):561-8. · 4.46 Impact Factor
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Kyeong-Min Lee,
Hye-Young Seo,
Mi Kyung Kim, Ae-Kyung Min,
Seong-Yeol Ryu,
Yoon-Nyun Kim,
Young Joo Park,
Hueng-Sik Choi,
Ki-Up Lee,
Wan-Ju Park,
Keun-Gyu Park,
In-Kyu Lee
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ABSTRACT: Angiotensin II is a major effector molecule in the development of cardiovascular disease. In vascular smooth muscle cells (VSMCs), angiotensin II promotes cellular proliferation and extracellular matrix accumulation through the upregulation of plasminogen activator inhibitor-1 (PAI-1) expression. Previously, we demonstrated that small heterodimer partner (SHP) represses PAI-1 expression in the liver through the inhibition of TGF-β signaling pathways. Here, we investigated whether SHP inhibited angiotensin II-stimulated PAI-1 expression in VSMCs. Adenovirus-mediated overexpression of SHP (Ad-SHP) in VSMCs inhibited angiotensin II- and TGF-β-stimulated PAI-1 expression. Ad-SHP also inhibited angiotensin II-, TGF-β- and Smad3-stimulated PAI-1 promoter activity, and angiotensin II-stimulated AP-1 activity. The level of PAI-1 expression was significantly higher in VSMCs of SHP-/- mice than wild type mice. Moreover, loss of SHP increased PAI-1 mRNA expression after angiotensin II treatment. These results suggest that SHP inhibits PAI-1 expression in VSMCs through the suppression of TGF-β/Smad3 and AP-1 activity. Thus, agents that target the induction of SHP expression in VSMCs might help prevent the development and progression of atherosclerosis.
Experimental and Molecular Medicine 11/2009; · 2.48 Impact Factor
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Keun-Gyu Park, Ae-Kyung Min,
Eun Hee Koh,
Hyoun Sik Kim,
Mi-Ok Kim,
Hye-Sun Park,
Yong-Deuk Kim,
Tae-Seung Yoon,
Byoung Kuk Jang,
Jae Seok Hwang,
Jae Bum Kim,
Hueng-Sik Choi,
Joong-Yeol Park,
In-Kyu Lee,
Ki-Up Lee
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ABSTRACT: Fatty liver is common in obese subjects with insulin resistance. Hepatic expression of sterol regulatory element binding protein-1c (SREBP-1c), which plays a major role in hepatic steatosis, is regulated by multiple factors, including insulin, adenosine monophosphate-activated protein kinase (AMPK), liver X receptors (LXRs), and specificity protein 1. Alpha-lipoic acid (ALA), a naturally occurring antioxidant, has been shown to decrease lipid accumulation in skeletal muscle by activating AMPK. Here we show that ALA decreases hepatic steatosis and SREBP-1c expression in rats on a high fat diet or given an LXR agonist. ALA increased AMPK phosphorylation in the liver and in cultured liver cells, and dominant-negative AMPK partially prevented ALA-induced suppression of insulin-stimulated SREBP-1c expression. ALA also inhibited DNA-binding activity and transcriptional activity of both specificity protein 1 and LXR. CONCLUSION: These results show that ALA prevents fatty liver disease through multiple mechanisms, and suggest that ALA can be used to prevent the development and progression of nonalcoholic fatty liver disease in patients with insulin resistance.
Hepatology 12/2008; 48(5):1477-86. · 11.66 Impact Factor
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Hye-Young Seo,
Yong Deuk Kim,
Kyeong-Min Lee, Ae-Kyung Min,
Mi-Kyung Kim,
Hye-Soon Kim,
Kyu-Chang Won,
Joong-Yeol Park,
Ki-Up Lee,
Hueng-Sik Choi,
Keun-Gyu Park,
In-Kyu Lee
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ABSTRACT: The highly developed endoplasmic reticulum (ER) structure of pancreatic beta-cells is a key factor in beta-cell function. Here we examined whether ER stress-induced activation of activating transcription factor (ATF)-6 impairs insulin gene expression via up-regulation of the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), which has been shown to play a role in beta-cell dysfunction. We examined whether ER stress decreases insulin gene expression, and this process is mediated by ATF6. A small interfering RNA that targeted SHP was used to determine whether the effect of ATF6 on insulin gene expression is mediated by SHP. We also measured the expression level of ATF6 in pancreatic islets in Otsuka Long Evans Tokushima Fatty rats, a rodent model of type 2 diabetes. High glucose concentration (30 mmol/liter glucose) increased ER stress in INS-1 cells. ER stress induced by tunicamycin, thapsigargin, or dithiotreitol decreased insulin gene transcription. ATF6 inhibited insulin promoter activity, whereas X-box binding protein-1 and ATF4 did not. Adenovirus-mediated overexpression of active form of ATF6 in INS-1 cells impaired insulin gene expression and secretion. ATF6 also down-regulated pancreatic duodenal homeobox factor-1 and RIPE3b1/MafA gene expression and repressed the cooperative action of pancreatic duodenal homeobox factor-1, RIPE3b1/MafA, and beta-cell E box transactivator 2 in stimulating insulin transcription. The ATF6-induced suppression of insulin gene expression was associated with up-regulation of SHP gene expression. Finally, we found that expression of ATF6 was increased in the pancreatic islets of diabetic Otsuka Long Evans Tokushima Fatty rats, compared with their lean, nondiabetic counterparts, Long-Evans Tokushima Otsuka rats. Collectively, this study shows that ER stress-induced activation of ATF6 plays an important role in the development of beta-cell dysfunction.
Endocrinology 06/2008; 149(8):3832-41. · 4.46 Impact Factor
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Ae-Kyung Min
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ABSTRACT: The purpose of this study is to find an intervention that will help alleviate women's signs and discomforts associated with premenstrual syndrome (PMS). As the social activities of women increase, eliminating PMS becomes increasingly important for many Korean women. A possible health care countermeasure for PMS is to assess PMS at an early stage; clarify the premenstrual signs, symptoms, and tensions; and afterward alleviate the premenstrual signs and discomforts. Related educational programs have been found to be effective interventions. Studies in Korea until now generally have focused on premenstrual signs and discomforts. This study, in contrast, was carried out in order to find women who have physical, mental, emotional, and behavioral discomforts due to PMS, then to provide them with an educational program, and eventually to establish an intervention that would help alleviate their premenstrual signs and discomforts.
Health Care For Women International 23(5):503-11. · 0.63 Impact Factor
