PRD125, a potent and selective inhibitor of sterol O-acyltransferase 2 markedly reduces hepatic cholesteryl ester accumulation and improves liver function in lysosomal acid lipase-deficient mice

Adam M. Lopez, Jen Chieh Chuang, Kenneth S. Posey, Taichi Ohshiro, Hiroshi Tomoda, Lawrence L. Rudel, Stephen D. Turley

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

In most organs, the bulk of cholesterol is unesterified, although nearly all possess a varying capability of esterifying cholesterol through the action of either sterol O-acyltransferase (SOAT) 1 or, in the case of hepatocytes and enterocytes, SOAT2. Esterified cholesterol (EC) carried in plasma lipoproteins is hydrolyzed by lysosomal acid lipase (LAL) when they are cleared from the circulation. Loss-of-function mutations in LIPA, the gene that encodes LAL, result in Wolman disease or cholesteryl ester storage disease (CESD). Hepatomegaly and a massive increase in tissue EC levels are hallmark features of both disorders. While these conditions can be corrected with enzyme replacement therapy, the question arose as to whether pharmacological inhibition of SOAT2 might reduce tissue EC accretion in CESD. When weaned at 21 days, Lal-/- mice, of either gender, had a whole liver cholesterol content that was 12- To 13-fold more than that of matching Lal-/- littermates (23 versus 1.8 mg, respectively). In Lal-/- males given the selective SOAT2 inhibitor PRD125 1,11-O-o-methylbenzylidene-7-O-p-cyanobenzoyl-1,7,11- Trideacetylpyripyropene A in their diet (∼10 mg/day per kg body weight) from 21 to 53 days, whole liver cholesterol content was 48.6 versus 153.7 mg in untreated 53-day-old Lal-/- mice. This difference reflected a 59% reduction in hepatic EC concentration (mg/g), combined with a 28% fall in liver mass. The treated mice also showed a 63% reduction in plasma alanine aminotransferase activity, in parallel with decisive falls in hepatic mRNA expression levels for multiple proteins that reflect macrophage presence and inflammation. These data implicate SOAT2 as a potential target in CESD management.

Original languageEnglish (US)
Pages (from-to)159-167
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume355
Issue number2
DOIs
StatePublished - Nov 1 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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