Effects of hepatocyte nuclear factor-1A and -4A on pancreatic stone protein/regenerating protein and C-reactive protein gene expression: implications for maturity-onset diabetes of the young

Journal of Translational Medicine

Maria M Byrne⁴  Jochen HM Prehn²  Rolf Graf³  Jasmin Schmid²  Seán M Kilbride²  Siobhan Bacon⁴  Caroline Bonner¹  Ma P Kyithar⁴ 

[1] Current address: Biotherapies for Diabetes, Univ Lille Nord de France, F-59000, Lille, France;Department of Physiology and Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland;Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Zurich, Switzerland;Department of Endocrinology, Mater Misericordiae University Hospital, 30 Eccles Street, Dublin 7, Ireland

关键词: Gene regulation;    HsCRP;    PSP/reg;    MODY;    HNF4A;    HNF1A;   

Others  :  827334
DOI  :  10.1186/1479-5876-11-156

 received in 2012-12-14, accepted in 2013-06-13,  发布年份 2013

【 摘 要 】

Background

There is a significant clinical overlap between patients with hepatocyte nuclear factor (HNF)-1A and HNF4A maturity-onset diabetes of the young (MODY), two forms of monogenic diabetes. HNF1A and HNF4A are transcription factors that control common and partly overlapping sets of target genes. We have previously shown that elevated serum pancreatic stone protein / regenerating protein A (PSP/reg1A) levels can be detected in subjects with HNF1A-MODY. In this study, we investigated whether PSP/reg is differentially regulated by HNF1A and HNF4A.

Methods

Quantitative real-time PCR (qPCR) and Western blotting were used to validate gene and protein expression in cellular models of HNF1A- and HNF4A-MODY. Serum PSP/reg1A levels and high-sensitivity C-reactive protein (hsCRP) were measured by ELISA in 31 HNF1A- and 9 HNF4A-MODY subjects. The two groups were matched for age, body mass index, diabetes duration, blood pressure, lipid profile and aspirin and statin use.

Results

Inducible repression of HNF1A and HNF4A function in INS-1 cells suggested that PSP/reg induction required HNF4A, but not HNF1A. In contrast, crp gene expression was significantly reduced by repression of HNF1A, but not HNF4A function. PSP/reg levels were significantly lower in HNF4A subjects when compared to HNF1A subjects [9.25 (7.85-12.85) ng/ml vs. 12.5 (10.61-17.87) ng/ml, U-test P = 0.025]. hsCRP levels were significantly lower in HNF1A-MODY [0.22 (0.17-0.35) mg/L] compared to HNF4A-MODY group [0.81 (0.38-1.41) mg/L, U-test P = 0.002], Parallel measurements of serum PSP/reg1A and hsCRP levels were able to discriminate HNF1A- and HNF4A-MODY subjects.

Conclusion

Our study demonstrates that two distinct target genes, PSP/reg and crp, are differentially regulated by HNF1A and HNF4A, and provides clinical proof-of-concept that serum PSP/reg1A and hsCRP levels may distinguish HNF1A-MODY from HNF4A-MODY subjects.

【 授权许可】

   
2013 Kyithar et al.; licensee BioMed Central Ltd.

【 图 表 】

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