Paraoxonase 1 Ameliorates Renal Lipotoxicity by Activating Lipophagy and Inhibiting Pyroptosis

Several studies in recent years have shown that lipid overload causes lipotoxic damage to the kidney, and oxidative stress, inflammation, and autophagic arrest are all important mechanisms of renal lip-otoxicity. However, effective measures with therapeutic effects on renal lipotoxicity are limited. The present study indicated the protective effect of the paraoxonase 1 (PON1) against renal lipotoxicity in high-fat diet-fed scavenger receptor class B type I-deficient (S1?-BI-/-) mice. The results showed that S1? -BI-/- mice exhibited significant renal pathologic characteristics, such as oxidative stress, inflam-mation, and fibrosis, under a normal chow diet, and were accompanied by dyslipidemia and reduced plasma PON1 activity and renal PON1 levels. PON1 overexpression significantly attenuated the above pathologic changes in the kidneys of S1? -BI-/- mice fed with a high-fat diet. Mechanistically, PON1 may ameliorate renal oxidative stress by reducing reactive oxygen species production, reduce renal lipid accumulation by inhibiting AKT/mechanistic target of rapamycin kinase pathway to activate lipophagy, and reduce the occurrence of inflammation and cell death by inhibiting Nod-like receptor family protein 3 inflammasome-mediated pyroptosis. The present study is the first to show that PON1 overexpression can effectively alleviate renal lipotoxicity injury, and PON1 may be a promising therapeutic strategy for the treatment of renal lipotoxicity-related diseases. (Am J Pathol 2022, 192: 1531-1545; https:// doi.org/10.1016/j.ajpath.2022.07.011)