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Patient Adipose Stem Cell-Derived Adipocytes Reveal Genetic Variation that Predicts Antidiabetic Drug Response.


ABSTRACT: Thiazolidinedione drugs (TZDs) target the transcriptional activity of peroxisome proliferator activated receptor ? (PPAR?) to reverse insulin resistance in type 2 diabetes, but side effects limit their clinical use. Here, using human adipose stem cell-derived adipocytes, we demonstrate that SNPs were enriched at sites of patient-specific PPAR? binding, which correlated with the individual-specific effects of the TZD rosiglitazone (rosi) on gene expression. Rosi induction of ABCA1, which regulates cholesterol metabolism, was dependent upon SNP rs4743771, which modulated PPAR? binding by influencing the genomic occupancy of its cooperating factor, NFIA. Conversion of rs4743771 from the inactive SNP allele to the active one by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated editing rescued PPAR? binding and rosi induction of ABCA1 expression. Moreover, rs4743771 is a major determinant of undesired serum cholesterol increases in rosi-treated diabetics. These data highlight human genetic variation that impacts PPAR? genomic occupancy and patient responses to antidiabetic drugs, with implications for developing personalized therapies for metabolic disorders.

SUBMITTER: Hu W 

PROVIDER: S-EPMC6368460 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Patient Adipose Stem Cell-Derived Adipocytes Reveal Genetic Variation that Predicts Antidiabetic Drug Response.

Hu Wenxiang W   Jiang Chunjie C   Guan Dongyin D   Dierickx Pieterjan P   Zhang Rong R   Moscati Arden A   Nadkarni Girish N GN   Steger David J DJ   Loos Ruth J F RJF   Hu Cheng C   Jia Weiping W   Soccio Raymond E RE   Lazar Mitchell A MA  

Cell stem cell 20190110 2


Thiazolidinedione drugs (TZDs) target the transcriptional activity of peroxisome proliferator activated receptor γ (PPARγ) to reverse insulin resistance in type 2 diabetes, but side effects limit their clinical use. Here, using human adipose stem cell-derived adipocytes, we demonstrate that SNPs were enriched at sites of patient-specific PPARγ binding, which correlated with the individual-specific effects of the TZD rosiglitazone (rosi) on gene expression. Rosi induction of ABCA1, which regulate  ...[more]

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