The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease

Abstract Insulin resistance and hepatic lipid accumulation constitute the metabolic underpinning of nonalcoholic steatohepatitis (NASH). We tested the hypothesis that saroglitazar, a PPAR α/γ agonist would improve NASH in the diet-induced animal model of NAFLD. Mice received chow diet and normal wat...

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Autores principales:	Divya P. Kumar, Rebecca Caffrey, Jonathon Marioneaux, Prasanna K. Santhekadur, Madhavi Bhat, Cristina Alonso, Srinivas V. Koduru, Binu Philip, Mukul R. Jain, Suresh R. Giri, Pierre Bedossa, Arun J. Sanyal
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d45c25c827cc43f29d734da65c99d76f
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spelling	oai:doaj.org-article:d45c25c827cc43f29d734da65c99d76f2021-12-02T17:52:33ZThe PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease10.1038/s41598-020-66458-z2045-2322https://doaj.org/article/d45c25c827cc43f29d734da65c99d76f2020-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-66458-zhttps://doaj.org/toc/2045-2322Abstract Insulin resistance and hepatic lipid accumulation constitute the metabolic underpinning of nonalcoholic steatohepatitis (NASH). We tested the hypothesis that saroglitazar, a PPAR α/γ agonist would improve NASH in the diet-induced animal model of NAFLD. Mice received chow diet and normal water (CDNW) or high fat western diet and ad lib sugar water (WDSW). After 12 weeks, WDSW fed mice were randomized to receive (1) WDSW alone, (2) WDSW + vehicle, (3) WDSW + pioglitazone or (4) WDSW + saroglitazar for an additional 12 weeks. Compared to mice on WDSW and vehicle controls, mice receiving WDSW + saroglitazar had lower weight, lower HOMA-IR, triglycerides, total cholesterol, and ALT. Saroglitazar improved steatosis, lobular inflammation, hepatocellular ballooning and fibrosis stage. NASH resolved in all mice receiving saroglitazar. These effects were at par with or superior to pioglitazone. Molecular analyses confirmed target engagement and reduced oxidative stress, unfolded protein response and fibrogenic signaling. Transcriptomic analysis further confirmed increased PPAR-target expression and an anti-inflammatory effect with saroglitazar. Lipidomic analyses demonstrated that saroglitazar also reduced triglycerides, diglycerides, sphingomyelins and ceramides. These preclinical data provide a strong rationale for developing saroglitazar for the treatment of NASH in humans.Divya P. KumarRebecca CaffreyJonathon MarioneauxPrasanna K. SanthekadurMadhavi BhatCristina AlonsoSrinivas V. KoduruBinu PhilipMukul R. JainSuresh R. GiriPierre BedossaArun J. SanyalNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-14 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Divya P. Kumar Rebecca Caffrey Jonathon Marioneaux Prasanna K. Santhekadur Madhavi Bhat Cristina Alonso Srinivas V. Koduru Binu Philip Mukul R. Jain Suresh R. Giri Pierre Bedossa Arun J. Sanyal The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease
description	Abstract Insulin resistance and hepatic lipid accumulation constitute the metabolic underpinning of nonalcoholic steatohepatitis (NASH). We tested the hypothesis that saroglitazar, a PPAR α/γ agonist would improve NASH in the diet-induced animal model of NAFLD. Mice received chow diet and normal water (CDNW) or high fat western diet and ad lib sugar water (WDSW). After 12 weeks, WDSW fed mice were randomized to receive (1) WDSW alone, (2) WDSW + vehicle, (3) WDSW + pioglitazone or (4) WDSW + saroglitazar for an additional 12 weeks. Compared to mice on WDSW and vehicle controls, mice receiving WDSW + saroglitazar had lower weight, lower HOMA-IR, triglycerides, total cholesterol, and ALT. Saroglitazar improved steatosis, lobular inflammation, hepatocellular ballooning and fibrosis stage. NASH resolved in all mice receiving saroglitazar. These effects were at par with or superior to pioglitazone. Molecular analyses confirmed target engagement and reduced oxidative stress, unfolded protein response and fibrogenic signaling. Transcriptomic analysis further confirmed increased PPAR-target expression and an anti-inflammatory effect with saroglitazar. Lipidomic analyses demonstrated that saroglitazar also reduced triglycerides, diglycerides, sphingomyelins and ceramides. These preclinical data provide a strong rationale for developing saroglitazar for the treatment of NASH in humans.
format	article
author	Divya P. Kumar Rebecca Caffrey Jonathon Marioneaux Prasanna K. Santhekadur Madhavi Bhat Cristina Alonso Srinivas V. Koduru Binu Philip Mukul R. Jain Suresh R. Giri Pierre Bedossa Arun J. Sanyal
author_facet	Divya P. Kumar Rebecca Caffrey Jonathon Marioneaux Prasanna K. Santhekadur Madhavi Bhat Cristina Alonso Srinivas V. Koduru Binu Philip Mukul R. Jain Suresh R. Giri Pierre Bedossa Arun J. Sanyal
author_sort	Divya P. Kumar
title	The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease
title_short	The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease
title_full	The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease
title_fullStr	The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease
title_full_unstemmed	The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease
title_sort	ppar α/γ agonist saroglitazar improves insulin resistance and steatohepatitis in a diet induced animal model of nonalcoholic fatty liver disease
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/d45c25c827cc43f29d734da65c99d76f
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The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease

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