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Luteolin Mitigates Diabetic Dyslipidemia in Rats by Modulating ACAT-2, PPARα, SREBP-2 Proteins, and Oxidative Stress

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Abstract

Diabetic dyslipidemia is a crucial link between type-2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular diseases (ASCVD). Natural biologically active substances have been advocated as complementary remedies for ASCVD and T2DM. Luteolin, a flavonoid, exhibits antioxidant, hypolipidemic, and antiatherogenic effects. Hence, we aimed to determine influence of luteolin on lipid homeostasis and hepatic damage in rats with T2DM induced by high-fat-diet (HFD) and streptozotocin (STZ). After being fed HFD for 10 days, male Wistar rats received 40 mg/kg STZ intraperitoneal injection on 11th day. Seventy-two hours later, hyperglycemic rats (fasting glucose > 200 mg/dL) were randomized into groups, and oral hydroxy-propyl-cellulose, atorvastatin (5 mg/kg), or luteolin (50 mg/kg or 100 mg/kg) administered daily, while continuing HFD for 28 days. Luteolin significantly ameliorated dyslipidemia levels and concomitantly improved atherogenic index of plasma in a dose-dependent manner. Increased levels of malondialdehyde and diminished levels of superoxide dismutase, catalase, and glutathione in HFD-STZ-diabetic rats were significantly regulated by luteolin. Luteolin significantly intensified PPARα expression while decreasing expression of acyl-coenzyme A:cholesterol acyltransferase-2 (ACAT-2) and sterol regulatory element binding protein-2 (SREBP-2) proteins. Moreover, luteolin effectively alleviated hepatic impairment in HFD-STZ-diabetic rats to near-normal control levels. The findings of the present study expound mechanisms by which luteolin mitigated diabetic dyslipidemia and alleviated hepatic impairment in HFD-STZ-diabetic rats by amelioration of oxidative stress, modulation of PPARα expression, and downregulation of ACAT-2 and SREBP-2. In conclusion, our results imply that luteolin may be efficacious in management of dyslipidemia in T2DM, and future research may be essential to substantiate our findings.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors are grateful to Dr. Natesan Pazhanivel for his inputs regarding the histopathological examination of the liver.

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Authors and Affiliations

  1. Department of Pharmacology, Saveetha Medical College & Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai, 602105, Tamil Nadu, India

    Syed Ilyas Shehnaz

  2. Centre for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, 600077, Tamil Nadu, India

    Anitha Roy

  3. Department of Research and Development, Saveetha Institute of Medical and Technical Sciences, Chennai, 602105, Tamil Nadu, India

    Rajagopalan Vijayaraghavan & Senthilkumar Sivanesan

  4. Department of Biosciences, Institute of Biotechnology, Saveetha Institute of Medical and Technical Sciences, Chennai, 602105, Tamil Nadu, India

    Senthilkumar Sivanesan

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  1. Syed Ilyas Shehnaz
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Contributions

Syed Ilyas Shehnaz (S. I. S.) conceived and designed the experiments, guided by Anitha Roy. S. I. S. performed the experiments, guided by Rajagopalan Vijayaraghavan (R. V.). S. I. S. and R. V. performed the statistical analysis. The first draft of the manuscript was written by S. I. S. with contributions to the methodology section by R. V. and Senthilkumar Sivanesan. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Syed Ilyas Shehnaz.

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Ethics approval in handling the rats and conducting the animal studies was obtained from the Institutional Animal Ethics Committee of Saveetha Institute of Medical and Technical Sciences (SIMATS) with an approval reference number of (SU/CLAR/RD/007/2019, dated 21 December 2019).

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Shehnaz, S.I., Roy, A., Vijayaraghavan, R. et al. Luteolin Mitigates Diabetic Dyslipidemia in Rats by Modulating ACAT-2, PPARα, SREBP-2 Proteins, and Oxidative Stress. Appl Biochem Biotechnol 195, 4893–4914 (2023). https://doi.org/10.1007/s12010-023-04544-4

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