GPR119 activation by DA-1241 alleviates hepatic and systemic inflammation in MASH mice through inhibition of NFκB signaling
Abstracts: Background and purpose: GPR119 activation has been suggested to improve hyperglycemia, dyslipidemia and hepatic steatosis. But its therapeutic potential for metabolic dysfunction-associated steatohepatitis (MASH) are underexplored. Here, we investigated the effects of DA-1241, a novel GP...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223011368 |
| _version_ | 1797686863052406784 |
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| author | Seung-Ho Lee Hansu Park Eun-Kyoung Yang Bo Ram Lee Il-Hoon Jung Tae-Hyoung Kim Moon Jung Goo Yuna Chae Mi-Kyung Kim |
| author_facet | Seung-Ho Lee Hansu Park Eun-Kyoung Yang Bo Ram Lee Il-Hoon Jung Tae-Hyoung Kim Moon Jung Goo Yuna Chae Mi-Kyung Kim |
| author_sort | Seung-Ho Lee |
| collection | DOAJ |
| description | Abstracts: Background and purpose: GPR119 activation has been suggested to improve hyperglycemia, dyslipidemia and hepatic steatosis. But its therapeutic potential for metabolic dysfunction-associated steatohepatitis (MASH) are underexplored. Here, we investigated the effects of DA-1241, a novel GPR119 agonist, on MASH and explored its underlying mechanism of anti-inflammatory effects. Experimental approach: The in vivo anti-MASH effect was assessed by examining the preventive effect in MS-MASH and Ob-MASH mice and the therapeutic effect in MASH with severe hyperglycemia and diet-induced obese (DIO)-MASH mice. Histological and biochemical changes in liver tissue were assessed. Both plasma and hepatic biomarkers related to inflammation and fibrosis were comprehensively analyzed. To understand its mode of action, changes in NFκB signaling were determined in HepG2 and THP-1 cells. Key results: DA-1241 attenuated MASH progression and alleviated the MASH phenotypes in MASH mouse models with different etiologies, regardless of glucose-lowering activity. In DIO-MASH mice, DA-1241 significantly reduced biochemical parameters related to steatosis, inflammation and fibrosis in the liver with reduced plasma liver enzymes. When used in combination with a dipeptidyl peptidase 4 (DPP4) inhibitor, DA-1241 further improved the MASH phenotype by increasing endogenous glucagon-like peptide-1 effect. Notably, DA-1241 alone and in combination reduced liver inflammation and restored inflammation-related hepatic gene expression, leading to remission of systemic inflammation as assessed by plasma inflammatory cytokines and chemokines. We demonstrated that DA-1241 reduces macrophage differentiation through downregulation of NFκB signaling by activating GPR119. Conclusion: Our data suggest the therapeutic potential of DA-1241, alone and in combination with a DPP4 inhibitor, for MASH. |
| first_indexed | 2024-03-12T01:10:44Z |
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| id | doaj.art-620a40766e8044aa946f865096d410a3 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-12T01:10:44Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-620a40766e8044aa946f865096d410a32023-09-14T04:52:43ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-10-01166115345GPR119 activation by DA-1241 alleviates hepatic and systemic inflammation in MASH mice through inhibition of NFκB signalingSeung-Ho Lee0Hansu Park1Eun-Kyoung Yang2Bo Ram Lee3Il-Hoon Jung4Tae-Hyoung Kim5Moon Jung Goo6Yuna Chae7Mi-Kyung Kim8Research Headquarter, Dong-A ST Co., Ltd., Yongin 17073, Republic of KoreaResearch Headquarter, Dong-A ST Co., Ltd., Yongin 17073, Republic of KoreaResearch Headquarter, Dong-A ST Co., Ltd., Yongin 17073, Republic of KoreaResearch Headquarter, Dong-A ST Co., Ltd., Yongin 17073, Republic of KoreaResearch Headquarter, Dong-A ST Co., Ltd., Yongin 17073, Republic of KoreaResearch Headquarter, Dong-A ST Co., Ltd., Yongin 17073, Republic of KoreaResearch Headquarter, Dong-A ST Co., Ltd., Yongin 17073, Republic of KoreaResearch Headquarter, Dong-A ST Co., Ltd., Yongin 17073, Republic of KoreaCorrespondence to: Dong-A ST Co., Ltd., 21, Geumhwa-ro 105Beon-gil, Giheung-gu 17073, Republic of Korea.; Research Headquarter, Dong-A ST Co., Ltd., Yongin 17073, Republic of KoreaAbstracts: Background and purpose: GPR119 activation has been suggested to improve hyperglycemia, dyslipidemia and hepatic steatosis. But its therapeutic potential for metabolic dysfunction-associated steatohepatitis (MASH) are underexplored. Here, we investigated the effects of DA-1241, a novel GPR119 agonist, on MASH and explored its underlying mechanism of anti-inflammatory effects. Experimental approach: The in vivo anti-MASH effect was assessed by examining the preventive effect in MS-MASH and Ob-MASH mice and the therapeutic effect in MASH with severe hyperglycemia and diet-induced obese (DIO)-MASH mice. Histological and biochemical changes in liver tissue were assessed. Both plasma and hepatic biomarkers related to inflammation and fibrosis were comprehensively analyzed. To understand its mode of action, changes in NFκB signaling were determined in HepG2 and THP-1 cells. Key results: DA-1241 attenuated MASH progression and alleviated the MASH phenotypes in MASH mouse models with different etiologies, regardless of glucose-lowering activity. In DIO-MASH mice, DA-1241 significantly reduced biochemical parameters related to steatosis, inflammation and fibrosis in the liver with reduced plasma liver enzymes. When used in combination with a dipeptidyl peptidase 4 (DPP4) inhibitor, DA-1241 further improved the MASH phenotype by increasing endogenous glucagon-like peptide-1 effect. Notably, DA-1241 alone and in combination reduced liver inflammation and restored inflammation-related hepatic gene expression, leading to remission of systemic inflammation as assessed by plasma inflammatory cytokines and chemokines. We demonstrated that DA-1241 reduces macrophage differentiation through downregulation of NFκB signaling by activating GPR119. Conclusion: Our data suggest the therapeutic potential of DA-1241, alone and in combination with a DPP4 inhibitor, for MASH.http://www.sciencedirect.com/science/article/pii/S0753332223011368GPR119DA-1241MASHInflammationNFκB |
| spellingShingle | Seung-Ho Lee Hansu Park Eun-Kyoung Yang Bo Ram Lee Il-Hoon Jung Tae-Hyoung Kim Moon Jung Goo Yuna Chae Mi-Kyung Kim GPR119 activation by DA-1241 alleviates hepatic and systemic inflammation in MASH mice through inhibition of NFκB signaling Biomedicine & Pharmacotherapy GPR119 DA-1241 MASH Inflammation NFκB |
| title | GPR119 activation by DA-1241 alleviates hepatic and systemic inflammation in MASH mice through inhibition of NFκB signaling |
| title_full | GPR119 activation by DA-1241 alleviates hepatic and systemic inflammation in MASH mice through inhibition of NFκB signaling |
| title_fullStr | GPR119 activation by DA-1241 alleviates hepatic and systemic inflammation in MASH mice through inhibition of NFκB signaling |
| title_full_unstemmed | GPR119 activation by DA-1241 alleviates hepatic and systemic inflammation in MASH mice through inhibition of NFκB signaling |
| title_short | GPR119 activation by DA-1241 alleviates hepatic and systemic inflammation in MASH mice through inhibition of NFκB signaling |
| title_sort | gpr119 activation by da 1241 alleviates hepatic and systemic inflammation in mash mice through inhibition of nfκb signaling |
| topic | GPR119 DA-1241 MASH Inflammation NFκB |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223011368 |
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