Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models
Background & Aims: Non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) are common clinico‐pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH....
| Main Authors: | , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2019
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| Online Access: | https://hdl.handle.net/10356/106322 http://hdl.handle.net/10220/49606 |
| _version_ | 1811693824088473600 |
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| author | Jain, Mukul R. Giri, Suresh R. Bhoi, Bibhuti Trivedi, Chitrang Rath, Akshyaya Rathod, Rohan Ranvir, Ramchandra Kadam, Shekhar Patel, Hiren Swain, Prabodha Roy, Sib Sankar Das, Nabanita Karmakar, Eshani Wahli, Walter Patel, Pankaj R. |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Jain, Mukul R. Giri, Suresh R. Bhoi, Bibhuti Trivedi, Chitrang Rath, Akshyaya Rathod, Rohan Ranvir, Ramchandra Kadam, Shekhar Patel, Hiren Swain, Prabodha Roy, Sib Sankar Das, Nabanita Karmakar, Eshani Wahli, Walter Patel, Pankaj R. |
| author_sort | Jain, Mukul R. |
| collection | NTU |
| description | Background & Aims: Non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) are common clinico‐pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH. Methods & Results: HepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFα, IL1β and IL6). These effects were blocked by saroglitazar, pioglitazone and fenofibrate (all tested at 10μM concentration). Furthermore, these agents reversed PA‐mediated changes in mitochondrial dysfunction, ATP production, NFkB phosphorylation and stellate cell activation in HepG2 and HepG2‐LX2 Coculture studies. In mice with choline‐deficient high‐fat diet‐induced NASH, saroglitazar reduced hepatic steatosis, inflammation, ballooning and prevented development of fibrosis. It also reduced serum alanine aminotransferase, aspartate aminotransferase and expression of inflammatory and fibrosis biomarkers. In this model, the reduction in the overall NAFLD activity score by saroglitazar (3 mg/kg) was significantly more prominent than pioglitazone (25 mg/kg) and fenofibrate (100 mg/kg). Pioglitazone and fenofibrate did not show any improvement in steatosis, but partially improved inflammation and liver function. Antifibrotic effect of saroglitazar (4 mg/kg) was also observed in carbon tetrachloride‐induced fibrosis model. Conclusions: Saroglitazar, a dual PPARα/γ agonist with predominant PPARα activity, shows an overall improvement in NASH. The effects of saroglitazar appear better than pure PPARα agonist, fenofibrate and PPARγ agonist pioglitazone. |
| first_indexed | 2024-10-01T06:57:49Z |
| format | Journal Article |
| id | ntu-10356/106322 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:57:49Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/1063222020-11-01T05:26:21Z Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models Jain, Mukul R. Giri, Suresh R. Bhoi, Bibhuti Trivedi, Chitrang Rath, Akshyaya Rathod, Rohan Ranvir, Ramchandra Kadam, Shekhar Patel, Hiren Swain, Prabodha Roy, Sib Sankar Das, Nabanita Karmakar, Eshani Wahli, Walter Patel, Pankaj R. Lee Kong Chian School of Medicine (LKCMedicine) NAFLD Science::Medicine Dual‐PPAR Agonist Background & Aims: Non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) are common clinico‐pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH. Methods & Results: HepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFα, IL1β and IL6). These effects were blocked by saroglitazar, pioglitazone and fenofibrate (all tested at 10μM concentration). Furthermore, these agents reversed PA‐mediated changes in mitochondrial dysfunction, ATP production, NFkB phosphorylation and stellate cell activation in HepG2 and HepG2‐LX2 Coculture studies. In mice with choline‐deficient high‐fat diet‐induced NASH, saroglitazar reduced hepatic steatosis, inflammation, ballooning and prevented development of fibrosis. It also reduced serum alanine aminotransferase, aspartate aminotransferase and expression of inflammatory and fibrosis biomarkers. In this model, the reduction in the overall NAFLD activity score by saroglitazar (3 mg/kg) was significantly more prominent than pioglitazone (25 mg/kg) and fenofibrate (100 mg/kg). Pioglitazone and fenofibrate did not show any improvement in steatosis, but partially improved inflammation and liver function. Antifibrotic effect of saroglitazar (4 mg/kg) was also observed in carbon tetrachloride‐induced fibrosis model. Conclusions: Saroglitazar, a dual PPARα/γ agonist with predominant PPARα activity, shows an overall improvement in NASH. The effects of saroglitazar appear better than pure PPARα agonist, fenofibrate and PPARγ agonist pioglitazone. Published version 2019-08-13T04:57:02Z 2019-12-06T22:09:06Z 2019-08-13T04:57:02Z 2019-12-06T22:09:06Z 2017 Journal Article Jain, M. R., Giri, S. R., Bhoi, B., Trivedi, C., Rath, A., Rathod, R., . . . Patel, P. R. (2018). Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver International, 38(6), 1084-1094. doi:10.1111/liv.13634 1478-3223 https://hdl.handle.net/10356/106322 http://hdl.handle.net/10220/49606 10.1111/liv.13634 en Liver International © 2017 Cadila Healthcare Ltd., Liver International Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. 11 p. application/pdf |
| spellingShingle | NAFLD Science::Medicine Dual‐PPAR Agonist Jain, Mukul R. Giri, Suresh R. Bhoi, Bibhuti Trivedi, Chitrang Rath, Akshyaya Rathod, Rohan Ranvir, Ramchandra Kadam, Shekhar Patel, Hiren Swain, Prabodha Roy, Sib Sankar Das, Nabanita Karmakar, Eshani Wahli, Walter Patel, Pankaj R. Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models |
| title | Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models |
| title_full | Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models |
| title_fullStr | Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models |
| title_full_unstemmed | Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models |
| title_short | Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models |
| title_sort | dual pparα γ agonist saroglitazar improves liver histopathology and biochemistry in experimental nash models |
| topic | NAFLD Science::Medicine Dual‐PPAR Agonist |
| url | https://hdl.handle.net/10356/106322 http://hdl.handle.net/10220/49606 |
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