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Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models.
Liver Int. 2018 06; 38(6):1084-1094.LI

Abstract

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.

Authors+Show Affiliations

Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India.Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India.Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India.Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India.Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India.Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India.Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India.Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India.Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India.Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India.Cell Biology and Physiology Division, Indian Institute of Chemical Biology, Kolkata, India.Cell Biology and Physiology Division, Indian Institute of Chemical Biology, Kolkata, India.Cell Biology and Physiology Division, Indian Institute of Chemical Biology, Kolkata, India.Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29164820

Citation

Jain, Mukul R., et al. "Dual PPARα/γ Agonist Saroglitazar Improves Liver Histopathology and Biochemistry in Experimental NASH Models." Liver International : Official Journal of the International Association for the Study of the Liver, vol. 38, no. 6, 2018, pp. 1084-1094.
Jain MR, Giri SR, Bhoi B, et al. Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int. 2018;38(6):1084-1094.
Jain, M. R., Giri, S. R., Bhoi, B., Trivedi, C., Rath, A., Rathod, R., Ranvir, R., Kadam, S., Patel, H., Swain, P., Roy, S. S., Das, N., Karmakar, E., Wahli, W., & Patel, P. R. (2018). Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver International : Official Journal of the International Association for the Study of the Liver, 38(6), 1084-1094. https://doi.org/10.1111/liv.13634
Jain MR, et al. Dual PPARα/γ Agonist Saroglitazar Improves Liver Histopathology and Biochemistry in Experimental NASH Models. Liver Int. 2018;38(6):1084-1094. PubMed PMID: 29164820.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. AU - Jain,Mukul R, AU - Giri,Suresh R, AU - Bhoi,Bibhuti, AU - Trivedi,Chitrang, AU - Rath,Akshyaya, AU - Rathod,Rohan, AU - Ranvir,Ramchandra, AU - Kadam,Shekhar, AU - Patel,Hiren, AU - Swain,Prabodha, AU - Roy,Sib Sankar, AU - Das,Nabanita, AU - Karmakar,Eshani, AU - Wahli,Walter, AU - Patel,Pankaj R, Y1 - 2017/12/14/ PY - 2017/02/21/received PY - 2017/11/13/accepted PY - 2017/11/23/pubmed PY - 2019/3/20/medline PY - 2017/11/23/entrez KW - Dual-PPAR agonist KW - NAFLD KW - NASH KW - Saroglitazar SP - 1084 EP - 1094 JF - Liver international : official journal of the International Association for the Study of the Liver JO - Liver Int. VL - 38 IS - 6 N2 - 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. SN - 1478-3231 UR - https://www.unboundmedicine.com/medline/citation/29164820/Dual_PPARα/γ_agonist_saroglitazar_improves_liver_histopathology_and_biochemistry_in_experimental_NASH_models_ L2 - https://doi.org/10.1111/liv.13634 DB - PRIME DP - Unbound Medicine ER -