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Paraoxonase 1 Ameliorates Renal Lipotoxicity by Activating Lipophagy and Inhibiting Pyroptosis

  • Qing Liu
    Affiliations
    Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
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  • Jing-Jie Xiao
    Affiliations
    Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
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  • Shan Wang
    Affiliations
    Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
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  • Ying Li
    Affiliations
    Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
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  • Li-Jiao Yang
    Affiliations
    Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
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  • Qian-Yu Lu
    Affiliations
    Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
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  • Xiao-Yan Wu
    Affiliations
    Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
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  • Jia Cao
    Affiliations
    Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
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  • Hong Yu
    Correspondence
    Address correspondence to Bai-Fang Zhang or Hong Yu, Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), 185 Donghu Rd., Wuhan 430071, China.
    Affiliations
    Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
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  • Bai-Fang Zhang
    Correspondence
    Address correspondence to Bai-Fang Zhang or Hong Yu, Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), 185 Donghu Rd., Wuhan 430071, China.
    Affiliations
    Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
    Search for articles by this author
      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 lipotoxicity. 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 (SR-BI−/−) mice. The results showed that SR-BI−/− mice exhibited significant renal pathologic characteristics, such as oxidative stress, inflammation, 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 SR-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.
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      References

        • Thongnak L.
        • Pongchaidecha A.
        • Lungkaphin A.
        Renal lipid metabolism and lipotoxicity in diabetes.
        Am J Med Sci. 2020; 359: 84-99
        • Engin A.B.
        What is lipotoxicity?.
        Adv Exp Med Biol. 2017; 960: 197-220
        • Moorhead J.F.
        • Chan M.K.
        • El-Nahas M.
        • Varghese Z.
        Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease.
        Lancet. 1982; 2: 1309-1311
        • Ruan X.Z.
        • Varghese Z.
        • Moorhead J.F.
        An update on the lipid nephrotoxicity hypothesis.
        Nat Rev Nephrol. 2009; 5: 713-721
        • Kong Y.
        • Zhao X.
        • Qiu M.
        • Lin Y.
        • Feng P.
        • Li S.
        • Liang B.
        • Zhu Q.
        • Huang H.
        • Li C.
        • Wang W.
        Tubular Mas receptor mediates lipid-induced kidney injury.
        Cell Death Dis. 2021; 12: 110
        • Opazo-Ríos L.
        • Mas S.
        • Marín-Royo G.
        • Mezzano S.
        • Gómez-Guerrero C.
        • Moreno J.A.
        • Egido J.
        Lipotoxicity and diabetic nephropathy: novel mechanistic insights and therapeutic opportunities.
        Int J Mol Sci. 2020; 21: 2632
        • Perła-Kaján J.
        • Jakubowski H.
        Paraoxonase 1 and homocysteine metabolism.
        Amino Acids. 2012; 43: 1405-1417
        • Primo-Parmo S.L.
        • Sorenson R.C.
        • Teiber J.
        • La Du B.N.
        The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family.
        Genomics. 1996; 33: 498-507
        • Rodrigo L.
        • Hernández A.F.
        • López-Caballero J.J.
        • Gil F.
        • Pla A.
        Immunohistochemical evidence for the expression and induction of paraoxonase in rat liver, kidney, lung and brain tissue: implications for its physiological role.
        Chem Biol Interact. 2001; 137: 123-137
        • Suszyńska-Zajczyk J.
        • Sikora M.
        • Jakubowski H.
        Paraoxonase 1 deficiency and hyperhomocysteinemia alter the expression of mouse kidney proteins involved in renal disease.
        Mol Genet Metab. 2014; 113: 200-206
        • Abraham P.
        • Sugumar E.
        Enhanced PON1 activity in the kidneys of cyclophosphamide treated rats may play a protective role as an antioxidant against cyclophosphamide induced oxidative stress.
        Arch Toxicol. 2008; 82: 237-238
        • Meneses M.J.
        • Silvestre R.
        • Sousa-Lima I.
        • Macedo M.P.
        Paraoxonase-1 as a regulator of glucose and lipid homeostasis: impact on the onset and progression of metabolic disorders.
        Int J Mol Sci. 2019; 20: 4049
        • Rom O.
        • Volkova N.
        • Jeries H.
        • Grajeda-Iglesias C.
        • Aviram M.
        Exogenous (pomegranate juice) or endogenous (paraoxonase1) antioxidants decrease triacylglycerol accumulation in mouse cardiovascular disease-related tissues.
        Lipids. 2018; 53: 1031-1041
        • Zhao X.J.
        • Liu L.C.
        • Guo C.
        • Shen W.W.
        • Cao J.
        • Du F.
        • Wu D.F.
        • Yu H.
        Hepatic paraoxonase 1 ameliorates dysfunctional high-density lipoprotein and atherosclerosis in scavenger receptor class B type I deficient mice.
        Ann Transl Med. 2021; 9: 1063
        • Xu Y.Y.
        • Du F.
        • Meng B.
        • Xie G.H.
        • Cao J.
        • Fan D.
        • Yu H.
        Hepatic overexpression of methionine sulfoxide reductase A reduces atherosclerosis in apolipoprotein E-deficient mice.
        J Lipid Res. 2015; 56: 1891-1900
        • Huby T.
        • Doucet C.
        • Dachet C.
        • Ouzilleau B.
        • Ueda Y.
        • Afzal V.
        • Rubin E.
        • Chapman M.J.
        • Lesnik P.
        Knockdown expression and hepatic deficiency reveal an atheroprotective role for SR-BI in liver and peripheral tissues.
        J Clin Invest. 2006; 116: 2767-2776
        • Martins Cardoso R.
        • Creemers E.
        • Absalah S.
        • Hoekstra M.
        • Gooris G.S.
        • Bouwstra J.A.
        • Van Eck M.
        Hyperalphalipoproteinemic scavenger receptor BI knockout mice exhibit a disrupted epidermal lipid barrier.
        Biochim Biophys Acta Mol Cell Biol Lipids. 2020; 1865: 158592
        • Van Eck M.
        • Twisk J.
        • Hoekstra M.
        • Van Rij B.T.
        • Van der Lans C.A.
        • Bos I.S.
        • Kruijt J.K.
        • Kuipers F.
        • Van Berkel T.J.
        Differential effects of scavenger receptor BI deficiency on lipid metabolism in cells of the arterial wall and in the liver.
        J Biol Chem. 2003; 278: 23699-23705
        • Ouweneel A.B.
        • Hoekstra M.
        • van der Wel E.J.
        • Schaftenaar F.H.
        • Snip O.S.C.
        • Hassan J.
        • Korporaal S.J.A.
        • Van Eck M.
        Hypercholesterolemia impairs megakaryopoiesis and platelet production in scavenger receptor BI knockout mice.
        Atherosclerosis. 2019; 282: 176-182
        • Zhou C.
        • Cao J.
        • Shang L.
        • Tong C.
        • Hu H.
        • Wang H.
        • Fan D.
        • Yu H.
        Reduced paraoxonase 1 activity as a marker for severe coronary artery disease.
        Dis Markers. 2013; 35: 97-103
        • Shao D.
        • Kolwicz Jr., S.C.
        • Wang P.
        • Roe N.D.
        • Villet O.
        • Nishi K.
        • Hsu Y.A.
        • Flint G.V.
        • Caudal A.
        • Wang W.
        • Regnier M.
        • Tian R.
        Increasing fatty acid oxidation prevents high-fat diet-induced cardiomyopathy through regulating Parkin-mediated mitophagy.
        Circulation. 2020; 142: 983-997
        • Koh E.H.
        • Yoon J.E.
        • Ko M.S.
        • Leem J.
        • Yun J.Y.
        • Hong C.H.
        • Cho Y.K.
        • Lee S.E.
        • Jang J.E.
        • Baek J.Y.
        • Yoo H.J.
        • Kim S.J.
        • Sung C.O.
        • Lim J.S.
        • Jeong W.I.
        • Back S.H.
        • Baek I.J.
        • Torres S.
        • Solsona-Vilarrasa E.
        • Conde de la Rosa L.
        • Garcia-Ruiz C.
        • Feldstein A.E.
        • Fernandez-Checa J.C.
        • Lee K.U.
        Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis.
        Gut. 2021; 70: 1954-1964
        • Li L.
        • Zeng X.
        • Liu Z.
        • Chen X.
        • Li L.
        • Luo R.
        • Liu X.
        • Zhang J.
        • Liu J.
        • Lu Y.
        • Cheng J.
        • Chen Y.
        Mesenchymal stromal cells protect hepatocytes from lipotoxicity through alleviation of endoplasmic reticulum stress by restoring SERCA activity.
        J Cell Mol Med. 2021; 25: 2976-2993
        • Zeng X.
        • Zhu M.
        • Liu X.
        • Chen X.
        • Yuan Y.
        • Li L.
        • Liu J.
        • Lu Y.
        • Cheng J.
        • Chen Y.
        Oleic acid ameliorates palmitic acid induced hepatocellular lipotoxicity by inhibition of ER stress and pyroptosis.
        Nutr Metab (Lond). 2020; 17: 11
        • García-Heredia A.
        • Kensicki E.
        • Mohney R.P.
        • Rull A.
        • Triguero I.
        • Marsillach J.
        • Tormos C.
        • Mackness B.
        • Mackness M.
        • Shih D.M.
        • Pedro-Botet J.
        • Joven J.
        • Sáez G.
        • Camps J.
        Paraoxonase-1 deficiency is associated with severe liver steatosis in mice fed a high-fat high-cholesterol diet: a metabolomic approach.
        J Proteome Res. 2013; 12: 1946-1955
        • Shokri Y.
        • Variji A.
        • Nosrati M.
        • Khonakdar-Tarsi A.
        • Kianmehr A.
        • Kashi Z.
        • Bahar A.
        • Bagheri A.
        • Mahrooz A.
        Importance of paraoxonase 1 (PON1) as an antioxidant and antiatherogenic enzyme in the cardiovascular complications of type 2 diabetes: genotypic and phenotypic evaluation.
        Diabetes Res Clin Pract. 2020; 161: 108067
        • Nezami N.
        • Ghorbanihaghjo A.
        • Argani H.
        • Safa J.
        • Rashtchizadeh N.
        • Vatankhah A.M.
        • Salari B.
        • Hajhosseini B.
        Lovastatin enhances paraoxonase enzyme activity and quells low-density lipoprotein susceptibility to oxidation in type 2 diabetic nephropathy.
        Clin Biochem. 2011; 44: 165-170
        • Miljkovic M.
        • Stefanovic A.
        • Vekic J.
        • Zeljkovic A.
        • Gojkovic T.
        • Simic-Ogrizovic S.
        • Bogavac-Stanojevic N.
        • Cerne D.
        • Ilic J.
        • Stefanovic I.
        • Jelic-Ivanovic Z.
        • Spasojevic-Kalimanovska V.
        • Kotur-Stevuljevic J.
        Activity of paraoxonase 1 (PON1) on HDL(2) and HDL(3) subclasses in renal disease.
        Clin Biochem. 2018; 60: 52-58
        • Gugliucci A.
        • Kinugasa E.
        • Kotani K.
        • Caccavello R.
        • Kimura S.
        Serum paraoxonase 1 (PON1) lactonase activity is lower in end-stage renal disease patients than in healthy control subjects and increases after hemodialysis.
        Clin Chem Lab Med. 2011; 49: 61-67
        • Sztanek F.
        • Seres I.
        • Harangi M.
        • Lőcsey L.
        • Padra J.
        • Paragh G.J.
        • Asztalos L.
        • Paragh G.
        Decreased paraoxonase 1 (PON1) lactonase activity in hemodialyzed and renal transplanted patients: a novel cardiovascular biomarker in end-stage renal disease.
        Nephrol Dial Transplant. 2012; 27: 2866-2872
        • Noeman S.A.
        • Hamooda H.E.
        • Baalash A.A.
        Biochemical study of oxidative stress markers in the liver, kidney and heart of high fat diet induced obesity in rats.
        Diabetol Metab Syndr. 2011; 3: 17
        • James R.W.
        • Brulhart-Meynet M.C.
        • Singh A.K.
        • Riederer B.
        • Seidler U.
        • Out R.
        • Van Berkel T.J.
        • Deakin S.
        The scavenger receptor class B, type I is a primary determinant of paraoxonase-1 association with high-density lipoproteins.
        Arterioscler Thromb Vasc Biol. 2010; 30: 2121-2127
        • Escasany E.
        • Izquierdo-Lahuerta A.
        • Medina-Gomez G.
        Underlying mechanisms of renal lipotoxicity in obesity.
        Nephron. 2019; 143: 28-32
        • Chen Y.Y.
        • Chen X.G.
        • Zhang S.
        Druggability of lipid metabolism modulation against renal fibrosis.
        Acta Pharmacol Sin. 2022; 43: 505-519
        • Jao T.M.
        • Nangaku M.
        • Wu C.H.
        • Sugahara M.
        • Saito H.
        • Maekawa H.
        • Ishimoto Y.
        • Aoe M.
        • Inoue T.
        • Tanaka T.
        • Staels B.
        • Mori K.
        • Inagi R.
        ATF6α downregulation of PPARα promotes lipotoxicity-induced tubulointerstitial fibrosis.
        Kidney Int. 2019; 95: 577-589
        • Han J.
        • Kaufman R.J.
        The role of ER stress in lipid metabolism and lipotoxicity.
        J Lipid Res. 2016; 57: 1329-1338
        • Sathyanarayan A.
        • Mashek M.T.
        • Mashek D.G.
        ATGL promotes autophagy/lipophagy via SIRT1 to control hepatic lipid droplet catabolism.
        Cell Rep. 2017; 19: 1-9
        • Han Y.
        • Xiong S.
        • Zhao H.
        • Yang S.
        • Yang M.
        • Zhu X.
        • Jiang N.
        • Xiong X.
        • Gao P.
        • Wei L.
        • Xiao Y.
        • Sun L.
        Lipophagy deficiency exacerbates ectopic lipid accumulation and tubular cells injury in diabetic nephropathy.
        Cell Death Dis. 2021; 12: 1031
        • Lee H.
        • Lee H.
        • Lim Y.
        Vitamin D(3) improves lipophagy-associated renal lipid metabolism and tissue damage in diabetic mice.
        Nutr Res. 2020; 80: 55-65
        • Furukawa S.
        • Fujita T.
        • Shimabukuro M.
        • Iwaki M.
        • Yamada Y.
        • Nakajima Y.
        • Nakayama O.
        • Makishima M.
        • Matsuda M.
        • Shimomura I.
        Increased oxidative stress in obesity and its impact on metabolic syndrome.
        J Clin Invest. 2004; 114: 1752-1761
        • Jaishy B.
        • Abel E.D.
        Lipids, lysosomes, and autophagy.
        J Lipid Res. 2016; 57: 1619-1635
        • Zheng H.J.
        • Zhang X.
        • Guo J.
        • Zhang W.
        • Ai S.
        • Zhang F.
        • Wang Y.
        • Liu W.J.
        Lysosomal dysfunction-induced autophagic stress in diabetic kidney disease.
        J Cell Mol Med. 2020; 24: 8276-8290
        • Yang H.
        • Gao Y.
        • Fan X.
        • Liu X.
        • Peng L.
        • Ci X.
        Oridonin sensitizes cisplatin-induced apoptosis via AMPK/Akt/mTOR-dependent autophagosome accumulation in A549 cells.
        Front Oncol. 2019; 9: 769
        • Zhang K.J.
        • Wu Q.
        • Jiang S.M.
        • Ding L.
        • Liu C.X.
        • Xu M.
        • Wang Y.
        • Zhou Y.
        • Li L.
        Pyroptosis: a new frontier in kidney diseases.
        Oxid Med Cell Longev. 2021; 2021: 6686617
        • Zhu X.
        • Li S.
        • Lin Q.
        • Shao X.
        • Wu J.
        • Zhang W.
        • Cai H.
        • Zhou W.
        • Jiang N.
        • Zhang Z.
        • Shen J.
        • Wang Q.
        • Ni Z.
        αKlotho protein has therapeutic activity in contrast-induced acute kidney injury by limiting NLRP3 inflammasome-mediated pyroptosis and promoting autophagy.
        Pharmacol Res. 2021; 167: 105531
        • Wu M.
        • Han W.
        • Song S.
        • Du Y.
        • Liu C.
        • Chen N.
        • Wu H.
        • Shi Y.
        • Duan H.
        NLRP3 deficiency ameliorates renal inflammation and fibrosis in diabetic mice.
        Mol Cell Endocrinol. 2018; 478: 115-125
        • Li Y.
        • Xia W.
        • Wu M.
        • Yin J.
        • Wang Q.
        • Li S.
        • Zhang A.
        • Huang S.
        • Zhang Y.
        • Jia Z.
        Activation of GSDMD contributes to acute kidney injury induced by cisplatin.
        Am J Physiol Renal Physiol. 2020; 318: F96-F106
        • Kim S.M.
        • Kim Y.G.
        • Kim D.J.
        • Park S.H.
        • Jeong K.H.
        • Lee Y.H.
        • Lim S.J.
        • Lee S.H.
        • Moon J.Y.
        Inflammasome-independent role of NLRP3 mediates mitochondrial regulation in renal injury.
        Front Immunol. 2018; 9: 2563