Sitagliptin alleviates renal steatosis and endoplasmic reticulum stress in high fat diet-induced obese rats by targeting SREBP-1/CD36 signaling pathway.

Autor: Elseweidy MM; Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt. Electronic address: mmelseweidy@pharmacy.zu.edu.eg., Asker ME; Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt., El-Zeiky RR; Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt., Elmaghraby AM; Histology and Cell Biology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt., Elrashidy RA; Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt. Electronic address: raelrashidy@zu.edu.eg.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2024 Aug 15; Vol. 977, pp. 176745. Date of Electronic Publication: 2024 Jun 14.
DOI: 10.1016/j.ejphar.2024.176745
Abstrakt: High fat diet (HFD) consumption can cause dysregulation of glucose and lipid metabolism, coupled with increased ectopic lipid deposition in renal tissue leading to steatosis and dysfunction. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor clinically used for type II diabetes therapy; however its effect on renal steatosis in obese state is still uncertain. Herein, obesity was induced by feeding male Wistar rats HFD for 18 weeks, thereafter received either drug vehicle, or sitagliptin (10 mg/kg, PO) along with HFD for further 6 weeks and compared with age-matched rats receiving normal chow diet (NCD). After 24 weeks, serum and kidneys were collected for histological and biochemical assessments. Compared to NCD-fed group, HFD-fed rats displayed marked weight gain, increased fat mass, insulin resistance, dyslipidemia, impaired kidney functions and renal histological alterations. Sitagliptin effectively ameliorated obesity and related metabolic perturbations and improved kidney architecture and function. There were increased levels of triglycerides and cluster of differentiation 36 (CD36) in kidneys of obese rats, that were lowered by sitagliptin therapy. Sitagliptin significantly repressed the expression of lipogenesis genes, while up-regulated genes involved in mitochondrial biogenesis and fatty acid oxidation in kidneys of HFD-fed rats. Sitagliptin was found to induce down-regulation of endoplasmic reticulum (ER) stress and apoptotic markers in kidneys of obese rats. These findings together may emphasize a novel concept that sitagliptin can be an effective therapeutic approach for halting obesity-related renal steatosis and CKD.
Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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