Paraoxonase 1 Ameliorates Renal Lipotoxicity by Activating Lipophagy and Inhibiting Pyroptosis

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Qing Liu1, Jing-Jie Xiao1, Shan Wang1

  • 1Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China.

The American Journal of Pathology
|August 13, 2022
PubMed

Insights

Paraoxonase 1 (PON1) protects kidneys from lipid overload damage. Overexpressing PON1 in scavenger receptor class B type I-deficient mice reduced kidney damage, suggesting PON1 as a potential therapy for kidney lipotoxicity.

Area of Science:

  • Nephrology
  • Metabolic Diseases
  • Biochemistry

Background:

  • Lipid overload causes kidney damage through oxidative stress, inflammation, and impaired autophagy.
  • Effective treatments for renal lipotoxicity remain limited.
  • Scavenger receptor class B type I deficiency (SR-BI-/-) exacerbates kidney pathology.

Purpose of the Study:

  • To investigate the protective role of paraoxonase 1 (PON1) against renal lipotoxicity.
  • To explore the therapeutic potential of PON1 in a mouse model of kidney lipotoxicity.

Main Methods:

  • Utilized high-fat diet-fed SR-BI-/- mice to model renal lipotoxicity.
  • Assessed renal pathology, oxidative stress, inflammation, and lipid accumulation.
  • Investigated the effect of PON1 overexpression on these parameters.
  • Examined underlying molecular mechanisms including AKT/mTOR and NLRP3 inflammasome pathways.

Main Results:

  • SR-BI-/- mice showed kidney damage, oxidative stress, inflammation, and fibrosis, with reduced PON1 activity.
  • PON1 overexpression significantly ameliorated these pathological changes in high-fat diet-fed SR-BI-/- mice.
  • PON1 reduced reactive oxygen species, inhibited AKT/mTOR to promote lipophagy, and suppressed NLRP3 inflammasome-mediated pyroptosis.

Conclusions:

  • PON1 demonstrates a significant protective effect against renal lipotoxicity.
  • PON1 overexpression alleviates kidney injury by reducing oxidative stress, lipid accumulation, inflammation, and pyroptosis.
  • PON1 represents a promising therapeutic target for treating renal lipotoxicity-related diseases.

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