Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagy
Objective: Abnormal autophagic function and activated inflammasomes are typical features in the liver of patients with non-alcoholic steatohepatitis (NASH). Here, we explored whether gemigliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor for treatment of type 2 diabetes, can induce autophagy and reg...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877823001400 |
| _version_ | 1827636096766312448 |
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| author | Youngmi Song Hyekyung Yang Juhee Kim Yoonjin Lee Sung-Ho Kim In-Gu Do Cheol-Young Park |
| author_facet | Youngmi Song Hyekyung Yang Juhee Kim Yoonjin Lee Sung-Ho Kim In-Gu Do Cheol-Young Park |
| author_sort | Youngmi Song |
| collection | DOAJ |
| description | Objective: Abnormal autophagic function and activated inflammasomes are typical features in the liver of patients with non-alcoholic steatohepatitis (NASH). Here, we explored whether gemigliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor for treatment of type 2 diabetes, can induce autophagy and regulate inflammasome activation as a potential NASH treatment independent of its anti-diabetic effect. Methods: Expression analysis was performed using human liver samples obtained from 18 subjects who underwent hepatectomy. We explored the function and mechanism of gemigliptin using a methionine- and choline-deficient diet (MCD)-induced NASH mouse model and HepG2 cells cultured in MCD-mimicking medium. Results: Autophagy was suppressed by marked decreases in the expression of ULK1 and LC3II/LC3I ratio in human NAFLD/NASH patients, a NASH mouse model, and HepG2 cells cultured with MCD-mimicking media. Surprisingly, we found that the expression of p-AMPK decreased in liver tissues from patients with steatosis but was restored in NASH patients. The expression of p-AMPK in the NASH mouse model was similar to that of the control group. Hence, these results indicate that autophagy was reduced in NASH via an AMPK-independent pathway. However, gemigliptin treatment attenuated lipid accumulation, inflammation, and fibrosis in the liver of MCD diet–fed mice with restoration of ULK1 expression and autophagy induction. In vitro, gemigliptin alleviated inflammasome activation through induction of ULK1-dependent autophagy. Furthermore, gemigliptin treatment upregulated ULK1 expression and activated AMPK even after siRNA-mediated knockdown of AMPKα1/2 and ULK1, respectively. Conclusions: Collectively, these results suggest that gemigliptin ameliorated NASH via AMPK-independent, ULK1-mediated effects on autophagy. |
| first_indexed | 2024-03-09T15:36:27Z |
| format | Article |
| id | doaj.art-d488041489a1447d94648f8e507925b7 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-09T15:36:27Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-d488041489a1447d94648f8e507925b72023-11-26T05:12:27ZengElsevierMolecular Metabolism2212-87782023-12-0178101806Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagyYoungmi Song0Hyekyung Yang1Juhee Kim2Yoonjin Lee3Sung-Ho Kim4In-Gu Do5Cheol-Young Park6Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South KoreaMedical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South KoreaMedical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South KoreaMedical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South KoreaLG Chem Life Sciences, Gangseo-gu, Seoul, South KoreaDepartment of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South KoreaMedical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea; Corresponding author. Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, South Korea.Objective: Abnormal autophagic function and activated inflammasomes are typical features in the liver of patients with non-alcoholic steatohepatitis (NASH). Here, we explored whether gemigliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor for treatment of type 2 diabetes, can induce autophagy and regulate inflammasome activation as a potential NASH treatment independent of its anti-diabetic effect. Methods: Expression analysis was performed using human liver samples obtained from 18 subjects who underwent hepatectomy. We explored the function and mechanism of gemigliptin using a methionine- and choline-deficient diet (MCD)-induced NASH mouse model and HepG2 cells cultured in MCD-mimicking medium. Results: Autophagy was suppressed by marked decreases in the expression of ULK1 and LC3II/LC3I ratio in human NAFLD/NASH patients, a NASH mouse model, and HepG2 cells cultured with MCD-mimicking media. Surprisingly, we found that the expression of p-AMPK decreased in liver tissues from patients with steatosis but was restored in NASH patients. The expression of p-AMPK in the NASH mouse model was similar to that of the control group. Hence, these results indicate that autophagy was reduced in NASH via an AMPK-independent pathway. However, gemigliptin treatment attenuated lipid accumulation, inflammation, and fibrosis in the liver of MCD diet–fed mice with restoration of ULK1 expression and autophagy induction. In vitro, gemigliptin alleviated inflammasome activation through induction of ULK1-dependent autophagy. Furthermore, gemigliptin treatment upregulated ULK1 expression and activated AMPK even after siRNA-mediated knockdown of AMPKα1/2 and ULK1, respectively. Conclusions: Collectively, these results suggest that gemigliptin ameliorated NASH via AMPK-independent, ULK1-mediated effects on autophagy.http://www.sciencedirect.com/science/article/pii/S2212877823001400GemigliptinDPP-4 inhibitorULK-1AutophagyNASHInflammasome |
| spellingShingle | Youngmi Song Hyekyung Yang Juhee Kim Yoonjin Lee Sung-Ho Kim In-Gu Do Cheol-Young Park Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagy Molecular Metabolism Gemigliptin DPP-4 inhibitor ULK-1 Autophagy NASH Inflammasome |
| title | Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagy |
| title_full | Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagy |
| title_fullStr | Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagy |
| title_full_unstemmed | Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagy |
| title_short | Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagy |
| title_sort | gemigliptin a dpp4 inhibitor ameliorates nonalcoholic steatohepatitis through amp activated protein kinase independent and ulk1 mediated autophagy |
| topic | Gemigliptin DPP-4 inhibitor ULK-1 Autophagy NASH Inflammasome |
| url | http://www.sciencedirect.com/science/article/pii/S2212877823001400 |
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