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Inflammation

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Saroglitazar Deactivates the Hepatic LPS/TLR4 Signaling Pathway and Ameliorates Adipocyte Dysfunction in Rats with High-Fat Emulsion/LPS Model-Induced Non-alcoholic Steatohepatitis

  • Noha F. Hassan
  • Somaia A. Nada
  • Azza Hassan
  • Mona R. El-AnsaryEmail author
  • Muhammad Y. Al-Shorbagy
  • Rania M. Abdelsalam
ORIGINAL ARTICLE
  • 39 Downloads

Abstract

The most epidemic liver disorder non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis and inflammation with hepatocellular damage. Recently, it is predictable to be the extensive cause for liver transplantation. The absence of an approved therapeutic agent for NASH is the reason for investigating saroglitazar (SAR) which showed promising effects as a dual PPAR-α/γ agonist in recent studies on NASH. Here, we aimed to investigate the effect of SAR on NASH induced in rats by the administration of high-fat emulsion (HFE) and small doses of lipopolysaccharides (LPS) for 5 weeks. Rats were divided into three groups: negative control group (saline and standard rodent chow), model group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p)), and SAR-treated group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p.) + SAR(4 mg/kg/day, oral gavage) starting at week 3.Treatment with SAR successfully ameliorated the damaging effects of HFE with LPS, by counteracting body weight gain and biochemically by normalization of liver function parameters activity, glucose, insulin, homeostasis model of assessment (HOMA-IR) score, lipid profile levels, and histopathological examination. Significant changes in adipokine levels were perceived, resulting in a significant decline in serum leptin and tumor necrosis factor-α (TNF-α) level concurrent with adiponectin normalization. The positive effects observed for SAR on NASH are due to the downregulation of the LPS/TLR4 pathway, as indicated by the suppression of hepatic Toll-like receptor 4 (TLR4), NF-κB, TNF-α, and transforming growth factor-β1 (TGF-β1) expression. In conclusion, this work verified that SAR ameliorates NASH through deactivation of the hepatic LPS/TLR4 pathway and inhibition of adipocyte dysfunction.

KEY WORDS

NASH lipopolysaccharide saroglitazar PPAR-α/γ agonist toll-like receptor 4 adipocyte 

Abbreviations

NASH

Non-alcoholic steatohepatitis

LPS

Lipopolysaccharide

HFE

High-fat emulsion

SAR

Saroglitazar

ALT

Alanine aminotransaminase

AST

Aspartate aminotransaminase

LDL

Low-density lipoprotein

NAFLD

Non-alcoholic fatty liver disease

HOMA

Homeostasis model of assessment

TLR4

Toll-like receptor 4

TNF-α

Tumor necrosis factor-α and

TGF-β1

Transforming growth factor-β1

NAFLD

Non-alcoholic fatty liver disease

HCC

Hepatocellular carcinoma

PPARs

Peroxisome proliferator-activator receptors

CMC

Carboxymethyl cellulose

FFAs

Free fatty acids

i.p

Intraperitoneal

H&E

Hematoxylin and eosin

LH

Lobular hepatitis

HB

Hepatocellular ballooning

PH

Portal hepatitis

Notes

Acknowledgments

This manuscript has been appreciatively scientifically edited by the Nature Research Editing Service through the Egyptian knowledge bank.

Compliance with Ethical Standards

Ethics Statement

Experimental design and animal handling procedures were approved by the Faculty of Pharmacy, Cairo University Research Ethics Committee, Cairo, Egypt: PT number (1742) and complied with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication no. 85–23, revised 1996). Every effort was made to minimize the number and suffering of animals used in this study.

Conflict of Interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. 1.Department of Pharmacology and Toxicology, Faculty of PharmacyModern University for Technology and InformationCairoEgypt
  2. 2.Department of Pharmacology and ToxicologyNational Research CentreGizaEgypt
  3. 3.Department of Pathology, Faculty of Veterinary MedicineCairo UniversityGizaEgypt
  4. 4.Department of Biochemistry, Faculty of PharmacyModern University for Technology and InformationCairoEgypt
  5. 5.Department of Pharmacology and Toxicology, Faculty of PharmacyCairo UniversityCairoEgypt
  6. 6.School of PharmacyNewgiza UniversityGizaEgypt

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