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DWN12088, A Prolyl-tRNA Synthetase Inhibitor, Alleviates Hepatic Injury in Nonalcoholic Steatohepatitis
Dong-Keon Lee, Su Ho Jo, Eun Soo Lee, Kyung Bong Ha, Na Won Park, Deok-Hoon Kong, Sang-In Park, Joon Seok Park, Choon Hee Chung
Diabetes Metab J. 2024;48(1):97-111.   Published online January 3, 2024
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Nonalcoholic steatohepatitis (NASH) is a liver disease caused by obesity that leads to hepatic lipoapoptosis, resulting in fibrosis and cirrhosis. However, the mechanism underlying NASH is largely unknown, and there is currently no effective therapeutic agent against it. DWN12088, an agent used for treating idiopathic pulmonary fibrosis, is a selective prolyl-tRNA synthetase (PRS) inhibitor that suppresses the synthesis of collagen. However, the mechanism underlying the hepatoprotective effect of DWN12088 is not clear. Therefore, we investigated the role of DWN12088 in NASH progression.
Mice were fed a chow diet or methionine-choline deficient (MCD)-diet, which was administered with DWN12088 or saline by oral gavage for 6 weeks. The effects of DWN12088 on NASH were evaluated by pathophysiological examinations, such as real-time quantitative reverse transcription polymerase chain reaction, immunoblotting, biochemical analysis, and immunohistochemistry. Molecular and cellular mechanisms of hepatic injury were assessed by in vitro cell culture.
DWN12088 attenuated palmitic acid (PA)-induced lipid accumulation and lipoapoptosis by downregulating the Rho-kinase (ROCK)/AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein-1c (SREBP-1c) and protein kinase R-like endoplasmic reticulum kinase (PERK)/α subunit of eukaryotic initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) signaling cascades. PA increased but DWN12088 inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 (Ser536, Ser276) and the expression of proinflammatory genes. Moreover, the DWN12088 inhibited transforming growth factor β (TGFβ)-induced pro-fibrotic gene expression by suppressing TGFβ receptor 1 (TGFβR1)/Smad2/3 and TGFβR1/glutamyl-prolyl-tRNA synthetase (EPRS)/signal transducer and activator of transcription 6 (STAT6) axis signaling. In the case of MCD-diet-induced NASH, DWN12088 reduced hepatic steatosis, inflammation, and lipoapoptosis and prevented the progression of fibrosis.
Our findings provide new insights about DWN12088, namely that it plays an important role in the overall improvement of NASH. Hence, DWN12088 shows great potential to be developed as a new integrated therapeutic agent for NASH.
Basic Research
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Beneficial Effects of a Curcumin Derivative and Transforming Growth Factor-β Receptor I Inhibitor Combination on Nonalcoholic Steatohepatitis
Kyung Bong Ha, Eun Soo Lee, Na Won Park, Su Ho Jo, Soyeon Shim, Dae-Kee Kim, Chan Mug Ahn, Choon Hee Chung
Diabetes Metab J. 2023;47(4):500-513.   Published online April 25, 2023
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Curcumin 2005-8 (Cur5-8), a derivative of curcumin, improves fatty liver disease via AMP-activated protein kinase activation and autophagy regulation. EW-7197 (vactosertib) is a small molecule inhibitor of transforming growth factor β (TGF-β) receptor I and may scavenge reactive oxygen species and ameliorate fibrosis through the SMAD2/3 canonical pathway. This study aimed to determine whether co-administering these two drugs having different mechanisms is beneficial.
Hepatocellular fibrosis was induced in mouse hepatocytes (alpha mouse liver 12 [AML12]) and human hepatic stellate cells (LX-2) using TGF-β (2 ng/mL). The cells were then treated with Cur5-8 (1 μM), EW-7197 (0.5 μM), or both. In animal experiments were also conducted during which, methionine-choline deficient diet, Cur5-8 (100 mg/kg), and EW-7197 (20 mg/kg) were administered orally to 8-week-old C57BL/6J mice for 6 weeks.
TGF-β-induced cell morphological changes were improved by EW-7197, and lipid accumulation was restored on the administration of EW-7197 in combination with Cur5-8. In a nonalcoholic steatohepatitis (NASH)-induced mouse model, 6 weeks of EW-7197 and Cur5-8 co-administration alleviated liver fibrosis and improved the nonalcoholic fatty liver disease (NAFLD) activity score.
Co-administering Cur5-8 and EW-7197 to NASH-induced mice and fibrotic hepatocytes reduced liver fibrosis and steatohepatitis while maintaining the advantages of both drugs. This is the first study to show the effect of the drug combination against NASH and NAFLD. Similar effects in other animal models will confirm its potential as a new therapeutic agent.


Citations to this article as recorded by  
  • Molecular Pathways Governing the Termination of Liver Regeneration
    Lianne R. de Haan, Rowan F. van Golen, Michal Heger, Martin Michel
    Pharmacological Reviews.2024; 76(3): 500.     CrossRef
Brief Report
Evogliptin, a Dipeptidyl Peptidase-4 Inhibitor, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice
Mi-Jin Kim, Na-young Kim, Yun-A Jung, Seunghyeong Lee, Gwon-Soo Jung, Jung-Guk Kim, In-Kyu Lee, Sungwoo Lee, Yeon-Kyung Choi, Keun-Gyu Park
Diabetes Metab J. 2020;44(1):186-192.   Published online October 31, 2019
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  • 10 Web of Science
  • 10 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   

Renal fibrosis is considered to be the final common outcome of chronic kidney disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors have demonstrated protective effects against diabetic kidney disease. However, the anti-fibrotic effect of evogliptin, a DPP-4 inhibitor, has not been studied. Here, we report the beneficial effects of evogliptin on unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Evogliptin attenuated UUO-induced renal atrophy and tubulointerstitial fibrosis. Immunohistochemistry and Western blotting demonstrated that evogliptin treatment inhibits pro-fibrotic gene expressions and extracellular matrix production. In vitro findings showed that the beneficial effects of evogliptin on renal fibrosis are mediated by inhibition of the transforming growth factor-β/Smad3 signaling pathway. The present study demonstrates that evogliptin is protective against UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of kidney disease of non-diabetic origin.


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  • Association Between DPP4 Inhibitor Use and the Incidence of Cirrhosis, ESRD, and Some Cancers in Patients With Diabetes
    Yewon Na, Soo Wan Kim, Ie Byung Park, Soo Jung Choi, Seungyoon Nam, Jaehun Jung, Dae Ho Lee
    The Journal of Clinical Endocrinology & Metabolism.2022; 107(11): 3022.     CrossRef
  • Evogliptin Directly Inhibits Inflammatory and Fibrotic Signaling in Isolated Liver Cells
    Hye-Young Seo, So-Hee Lee, Eugene Han, Jae Seok Hwang, Sol Han, Mi Kyung Kim, Byoung Kuk Jang
    International Journal of Molecular Sciences.2022; 23(19): 11636.     CrossRef
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    Hyunyee Yoon, Su Hee Cho, Yu Rim Seo, Kyung-Sang Yu, Sung Sup Park, Moon Jung Song
    Analytical Biochemistry.2021; 612: 113952.     CrossRef
  • Use of Anti-Diabetic Agents in Non-Diabetic Kidney Disease: From Bench to Bedside
    Sungjin Chung, Gheun-Ho Kim
    Life.2021; 11(5): 389.     CrossRef
  • Targeting Dermal Fibroblast Subtypes in Antifibrotic Therapy: Surface Marker as a Cellular Identity or a Functional Entity?
    Xin Huang, Yimin Khoong, Chengyao Han, Dai Su, Hao Ma, Shuchen Gu, Qingfeng Li, Tao Zan
    Frontiers in Physiology.2021;[Epub]     CrossRef
  • Efficacy and safety of evogliptin treatment in patients with type 2 diabetes: A multicentre, active‐controlled, randomized, double‐blind study with open‐label extension (the EVERGREEN study)
    Gyuri Kim, Soo Lim, Hyuk‐Sang Kwon, Ie B. Park, Kyu J. Ahn, Cheol‐Young Park, Su K. Kwon, Hye S. Kim, Seok W. Park, Sin G. Kim, Min K. Moon, Eun S. Kim, Choon H. Chung, Kang S. Park, Mikyung Kim, Dong J. Chung, Chang B. Lee, Tae H. Kim, Moon‐Kyu Lee
    Diabetes, Obesity and Metabolism.2020; 22(9): 1527.     CrossRef
  • Effect of Switching from Linagliptin to Teneligliptin Dipeptidyl Peptidase-4 Inhibitors in Older Patients with Type 2 Diabetes Mellitus

    Eugene Han, Minyoung Lee, Yong-ho Lee, Hye Soon Kim, Byung-wan Lee, Bong-Soo Cha, Eun Seok Kang
    Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy.2020; Volume 13: 4113.     CrossRef
  • Efficacy and safety of novel dipeptidyl-peptidase-4 inhibitor evogliptin in the management of type 2 diabetes mellitus: A meta-analysis
    Deep Dutta, Saptarshi Bhattacharya, Aishwarya Krishnamurthy, LokeshKumar Sharma, Meha Sharma
    Indian Journal of Endocrinology and Metabolism.2020; 24(5): 434.     CrossRef
Original Articles
Basic Research
Fibroblast Growth Factor 21 Attenuates Diabetes-Induced Renal Fibrosis by Negatively Regulating TGF-β-p53-Smad2/3-Mediated Epithelial-to-Mesenchymal Transition via Activation of AKT
Sundong Lin, Lechu Yu, Yongqing Ni, Lulu He, Xiaolu Weng, Xuemian Lu, Chi Zhang
Diabetes Metab J. 2020;44(1):158-172.   Published online October 28, 2019
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  • 38 Web of Science
  • 34 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   

Epithelial-to-mesenchymal transition (EMT) is required for renal fibrosis, which is a characteristic of diabetic nephropathy (DN). Our previous study demonstrated that fibroblast growth factor 21 (FGF21) prevented DN associated with the suppressing renal connective tissue growth factor expression, a key marker of renal fibrosis. Therefore, the effects of FGF21 on renal fibrosis in a DN mouse model and the underlying mechanisms were investigated in this study.


Type 1 diabetes mellitus was induced in C57BL/6J mice by intraperitoneal injections of multiple low doses of streptozotocin. Then, diabetic and non-diabetic mice were treated with or without FGF21 in the presence of pifithrin-α (p53 inhibitor) or 10-[4′-(N,N-Diethylamino)butyl]-2-chlorophenoxazine hydrochloride (10-DEBC) hydrochloride (Akt inhibitor) for 4 months.


DN was diagnosed by renal dysfunction, hypertrophy, tubulointerstitial lesions, and glomerulosclerosis associated with severe fibrosis, all of which were prevented by FGF21. FGF21 also suppressed the diabetes-induced renal EMT in DN mice by negatively regulating transforming growth factor beta (TGF-β)-induced nuclear translocation of Smad2/3, which is required for the transcription of multiple fibrotic genes. The mechanistic studies showed that FGF21 attenuated nuclear translocation of Smad2/3 by inhibiting renal activity of its conjugated protein p53, which carries Smad2/3 into the nucleus. Moreover pifithrin-α inhibited the FGF21-induced preventive effects on the renal EMT and subsequent renal fibrosis in DN mice. In addition, 10-DEBC also blocked FGF21-induced inhibition of renal p53 activity by phosphorylation of mouse double minute-2 homolog (MDM2).


FGF21 prevents renal fibrosis via negative regulation of the TGF-β/Smad2/3-mediated EMT process by activation of the Akt/MDM2/p53 signaling pathway.


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The Effect of alpha-Lipoic Acid on Proteinuria and Renal TGFbeta Expression in Obese Type 2 Diabetic Rat Model.
Seok Woo Kang, Seong Jin Lee, Dong Sun Kim, Tae Wha Kim
Korean Diabetes J. 2008;32(1):21-29.   Published online February 1, 2008
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AbstractAbstract PDF
It is well known that renal TGFbeta expression is related to the development of diabetic nephropathy. Alpha-lipoic acid (ALA), a potent antioxidant and cofactor of mitochondrial respiratory enzymes, can improve the insulin resistance and the vascular endothelial dysfunction, and suppresses the development of diabetic vascular complications. This study was undertaken to investigate whether ALA could reduce urinary protein excretion and renal TGFbeta protein expression in obese type 2 diabetes mellitus animal model, Otsuka Long-Evans Tokushima Fatty (OLETF) rat. METHODS: Obese 30 male OLETF rats were randomly divided to 3 groups at the age of 30 weeks. The rats in the Control group fed normal rat chow while the rats in the ALA group were fed with rat chow containing ALA (0.5% of food weight). Ten rats in the Pair-fed group were fed with normal rat chow, but were given the same amount of food as consumed by the ALA group. During 5 weeks of ALA feeding, food intake and body weight were checked in metabolic chamber. Blood glucose levels, HbA1c and urinary protein excretion were measured at 30 weeks and 35 weeks of age, and renal TGFbeta protein expression at 35 weeks of age was measured by Western blot and represented by relative unit (RU). Immunohistochemical staining for TGFbeta protein in renal tissue was also examined at 35 weeks of age. RESULTS: Food intake, body weight, blood glucose levels, HbA1c and urinary protein excretion among the Control, ALA and Pair-fed groups at 30 weeks of age were not different. At 35 weeks of age, food intake was significantly decreased in the ALA group than the Control group (Control group vs. ALA group, 27.7 +/- 1.1 g/day vs. 22.4 +/- 1.4 g/day, P < 0.001), and body weight was significantly decreased in the ALA group than the Control and Pair-fed groups (Control group: 694.4 +/- 10.3 g, ALA group: 600.4 +/- 7.4 g, Pair-fed group: 685.4 +/- 11.6 g, P < 0.001). Blood glucose levels were significantly decreased in the ALA group than the Control and Pair-fed groups (Control group: 157.7 +/- 4.6 mg/dL, ALA group: 130.7 +/- 4.8 mg/dL, Pair-fed group: 153.7 +/- 3.3 mg/dL, P < 0.001) although blood glucose levels from 30 weeks to 34 weeks of age and HbA1c at 35 weeks of age were not different among the groups. Urinary protein excretion and renal TGFbeta protein expression were significantly decreased in the ALA group than the Control and Pair-fed groups (urinary protein excretion, Control group: 5.033 +/- 0.254 mg/mgCr, ALA group: 3.633 +/- 0.303 mg/mgCr, Pair-fed group: 4.977 +/- 0.339 mg/mgCr, P < 0.001; renal TGFbeta protein expression, Control group: 7.09 +/- 0.17 RU, ALA group: 4.14 +/- 0.26 RU, Pair-fed group: 7.00 +/- 0.29 RU, P < 0.001). In the ALA group at 35 weeks of age, urinary protein excretion and renal TGFbeta protein expression were positively related in the Control, ALA and Pair-fed groups (Control group, r = 0.847, P = 0.002; ALA group, r = 0.954, P < 0.001; Pair-fed group, r = 0.858, P = 0.002). TGFbeta staining in glomeruli was observed in all groups but was decreased in the ALA group at 35 weeks of age. CONCLUSION: These results suggest that ALA may prevent the increase of food intake, body weight, blood glucose, urinary protein excretion and renal TGFbeta protein expression in obese type 2 diabetic rat model. The effect of ALA on diabetic nephropathy presented as proteinuria and renal TGFbeta expression in diabetic patients needs to be further clarified.


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