TY - JOUR
T1 - The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease
AU - Kumar, Divya P.
AU - Caffrey, Rebecca
AU - Marioneaux, Jonathon
AU - Santhekadur, Prasanna K.
AU - Bhat, Madhavi
AU - Alonso, Cristina
AU - Koduru, Srinivas V.
AU - Philip, Binu
AU - Jain, Mukul R.
AU - Giri, Suresh R.
AU - Bedossa, Pierre
AU - Sanyal, Arun J.
N1 - Funding Information:
We would like to thank Ms. Mary Ann Clements and EVMS Biorepository Histology Core for their expertise in preparing all tissue samples for subsequent histological analysis. This work was supported by a grant from Zydus, Cadila Health Care Limited to Sanyal Biotechnology LLC, Norfolk, Virginia, USA.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-020-66458-z
DO - 10.1038/s41598-020-66458-z
M3 - Article
C2 - 32518275
AN - SCOPUS:85086152369
VL - 10
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 9330
ER -