Sterol-O-acyltransferase-1 has a role in kidney disease associated with diabetes and Alport syndrome

Xiaochen Liu, Gloria Michelle Ducasa, Shamroop Kumar Mallela, Jin Ju Kim, Judith Molina, Alla Mitrofanova, Sydney Symone Wilbon, Mengyuan Ge, Antonio Fontanella, Christopher Pedigo, Javier Varona Santos, Robert G. Nelson, Yelena Drexler, Gabriel Contreras, Hassan Al-Ali, Sandra Merscher, Alessia Fornoni

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1275-1285
Number of pages11
JournalKidney international
Volume98
Issue number5
DOIs
StatePublished - Nov 2020

Keywords

  • Alport syndrome
  • SOAT1 inhibitor
  • cholesterol
  • diabetic kidney disease
  • podocyte injury
  • renal function

ASJC Scopus subject areas

  • Nephrology

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