TY - JOUR
T1 - Sterol-O-acyltransferase-1 has a role in kidney disease associated with diabetes and Alport syndrome
AU - Liu, Xiaochen
AU - Ducasa, Gloria Michelle
AU - Mallela, Shamroop Kumar
AU - Kim, Jin Ju
AU - Molina, Judith
AU - Mitrofanova, Alla
AU - Wilbon, Sydney Symone
AU - Ge, Mengyuan
AU - Fontanella, Antonio
AU - Pedigo, Christopher
AU - Santos, Javier Varona
AU - Nelson, Robert G.
AU - Drexler, Yelena
AU - Contreras, Gabriel
AU - Al-Ali, Hassan
AU - Merscher, Sandra
AU - Fornoni, Alessia
N1 - Funding Information:
AF and SM are inventors on pending or issued patents (PCT/US11/56272, PCT/US12/62594, PCT/US2019/041730, PCT/US2019/032215, PCT/US13/36484, and PCT 62/674,897) aimed at diagnosing or treating proteinuric kidney diseases. They stand to gain royalties from their future commercialization of these patents. AF is Vice President of L&F Health LLC and is consultant for ZyVersa Therapeutics, Inc. ZyVersa Therapeutics, Inc., has licensed worldwide rights to develop and commercialize hydroxypropyl-beta-cyclodextrin from L&F Research for the treatment of kidney disease. SM is a consultant for Kintai Therapeutics, Inc., and holds equity interest in L&F Research. AF and SM are supported by Hoffman-La Roche and by Boehringer Ingelheim. All the other authors declared no competing interests.
Funding Information:
AF and SM are supported by National Institutes of Health grants R01DK117599, R01DK104753, and R01CA227493, by Hoffmann-La Roche and the Alport Syndrome Foundation. AF is supported by U54DK083912, UM1DK100846, U01DK116101, and UL1TR000460 (Miami Clinical Translational Science Institute), and by Boehringer Ingelheim. We thank Dr. Hazel Szeto and Dr. Shaoyi Liu for processing and taking images of transmission electron microscopy of kidney cortices. We thank Dr. Armando Mendez for supporting the cholesterol efflux studies. We give a special thanks to the Katz family for their continuous support.
PY - 2020/11
Y1 - 2020/11
N2 - Defective cholesterol metabolism primarily linked to reduced ATP-binding cassette transporter A1 (ABCA1) expression is closely associated with the pathogenesis and progression of kidney diseases, including diabetic kidney disease and Alport Syndrome. However, whether the accumulation of free or esterified cholesterol contributes to progression in kidney disease remains unclear. Here, we demonstrate that inhibition of sterol-O-acyltransferase-1 (SOAT1), the enzyme at the endoplasmic reticulum that converts free cholesterol to cholesterol esters, which are then stored in lipid droplets, effectively reduced cholesterol ester and lipid droplet formation in human podocytes. Furthermore, we found that inhibition of SOAT1 in podocytes reduced lipotoxicity-mediated podocyte injury in diabetic kidney disease and Alport Syndrome in association with increased ABCA1 expression and ABCA1-mediated cholesterol efflux. In vivo, Soat1 deficient mice did not develop albuminuria or mesangial expansion at 10-12 months of age. However, Soat1 deficiency/inhibition in experimental models of diabetic kidney disease and Alport Syndrome reduced cholesterol ester content in kidney cortices and protected from disease progression. Thus, targeting SOAT1-mediated cholesterol metabolism may represent a new therapeutic strategy to treat kidney disease in patients with diabetic kidney disease and Alport Syndrome, like that suggested for Alzheimer's disease and cancer treatments.
AB - Defective cholesterol metabolism primarily linked to reduced ATP-binding cassette transporter A1 (ABCA1) expression is closely associated with the pathogenesis and progression of kidney diseases, including diabetic kidney disease and Alport Syndrome. However, whether the accumulation of free or esterified cholesterol contributes to progression in kidney disease remains unclear. Here, we demonstrate that inhibition of sterol-O-acyltransferase-1 (SOAT1), the enzyme at the endoplasmic reticulum that converts free cholesterol to cholesterol esters, which are then stored in lipid droplets, effectively reduced cholesterol ester and lipid droplet formation in human podocytes. Furthermore, we found that inhibition of SOAT1 in podocytes reduced lipotoxicity-mediated podocyte injury in diabetic kidney disease and Alport Syndrome in association with increased ABCA1 expression and ABCA1-mediated cholesterol efflux. In vivo, Soat1 deficient mice did not develop albuminuria or mesangial expansion at 10-12 months of age. However, Soat1 deficiency/inhibition in experimental models of diabetic kidney disease and Alport Syndrome reduced cholesterol ester content in kidney cortices and protected from disease progression. Thus, targeting SOAT1-mediated cholesterol metabolism may represent a new therapeutic strategy to treat kidney disease in patients with diabetic kidney disease and Alport Syndrome, like that suggested for Alzheimer's disease and cancer treatments.
KW - Alport syndrome
KW - cholesterol
KW - diabetic kidney disease
KW - podocyte injury
KW - renal function
KW - SOAT1 inhibitor
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U2 - 10.1016/j.kint.2020.06.040
DO - 10.1016/j.kint.2020.06.040
M3 - Article
C2 - 32739420
AN - SCOPUS:85093661206
VL - 98
SP - 1275
EP - 1285
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 5
ER -