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Trehalose-induced SIRT1/AMPK activation regulates SREBP-1c/PPAR-α to alleviate lipid accumulation in aged liver

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Abstract

Aging is associated with a disturbance in the regulation of the metabolic function of the liver, which increases the risk of liver and systemic diseases. Trehalose, a natural disaccharide, has been identified to reduce dyslipidemia, hepatic steatosis, and glucose intolerance. However, the roles of trehalose on lipid metabolism in aged liver are unclear which was investigated in this study. Thirty-two male Wistar rats were randomly allocated into four groups (n = 8). Two groups of aged (24 months) and young (4 months) rats were administered 2% trehalose solution orally for 30 days. Control groups of aged and young rats did not receive any treatment. At the end of the treatment period, blood samples and liver tissues were collected. Then the expression of SIRT1, AMPK, SREBP-1c, and PPAR-α and the level of AMPK phosphorylation (p-AMPK) were quantified by real-time polymerase chain reaction and western blotting. Moreover, biochemical parameters and the histopathology of livers were evaluated. Trehalose supplementation increased the level of SIRT1, p-AMPK, and PPAR-α, whereas the level of SREBP-1c was diminished in the liver of old animals. In addition, treatment with trehalose improved histopathological features of senescent livers. Taken together, our results show that old rats developed lipogenesis in the liver which was alleviated with trehalose. Therefore, trehalose may be an effective intervention to reduce the progression of aging-induced liver diseases.

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Data availability

All the data generated or analyzed during this study are included in this published article.

Abbreviations

ALT:

Alanine aminotransferase

AMP:

Adenosine monophosphate

AMPK:

AMP-activated protein kinase

APS:

Ammonium persulfate

AST:

Aspartate aminotransferase

ATP:

Adenosine triphosphate

ELISA:

Enzyme-linked immunosorbent assay

FSG:

Fasting serum glucose

HDL:

High-density lipoprotein

H&E:

Hematoxylin and eosin

HOMA-IR:

Homeostatic model assessment for insulin resistance

LDL:

Low-density lipoprotein

LKB1:

Liver kinase B1

NAD+ :

Nicotinamide adenine dinucleotide

NAFLD:

Non-alcoholic fatty liver disease

p-AMPK:

Phospho-AMPK

PCR:

Polymerase chain reaction

PPAR-α:

Peroxisome proliferator–activated receptor α

PVDF:

Polyvinylidene difluoride

SEM:

Standard error of the mean

SIRT1:

Sirtuin 1

SREBP-1c:

Sterol regulatory element–binding protein-1c

TEMED:

Tetramethylethylendiamine

VLDL:

Very-low-density lipoprotein

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Funding

This study was funded by Kerman University of Medical Sciences (Grant No. 400000186).

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Authors and Affiliations

  1. Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran

    Mahdis Rahimi Naiini, Bentolhoda Shafiei & Mahdieh Nazari-Robati

  2. Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran

    Beydolah Shahouzehi

  3. Department of Pathobiology, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran

    Shahrzad Azizi

Authors
  1. Mahdis Rahimi Naiini
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  2. Beydolah Shahouzehi
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  3. Shahrzad Azizi
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  4. Bentolhoda Shafiei
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  5. Mahdieh Nazari-Robati
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Contributions

Mahdieh Nazari‑Robati: conceptualization, funding acquisition, methodology, supervision; Mahdis Rahimi Naiini: investigation, data analysis, writing—original draft; Beydolah Shahouzehi: methodology, writing—review and editing; Shahrzad Azizi: investigation, data analysis; Bentolhoda Shafiei: investigation. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Mahdieh Nazari-Robati.

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Ethics approval

All animal experiments used in this research were approved by the ethics committee of Kerman University of Medical Sciences (IR.KMU.AH.REC.1400.074) and adhered to national guidelines for experiments involving laboratory animals.

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The authors declare no competing interests.

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Highlights

• Trehalose activated SIRT1/AMPK axis in aged liver.

• Trehalose regulated SREBP-1c/PPAR-α in aged liver.

• Trehalose ameliorated lipid accumulation in aged liver.

• Trehalose reduced histopathological scores in aged liver.

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Naiini, M.R., Shahouzehi, B., Azizi, S. et al. Trehalose-induced SIRT1/AMPK activation regulates SREBP-1c/PPAR-α to alleviate lipid accumulation in aged liver. Naunyn-Schmiedeberg's Arch Pharmacol 397, 1061–1070 (2024). https://doi.org/10.1007/s00210-023-02644-w

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