<i>PNLIPRP1</i> Hypermethylation in Exocrine Pancreas Links Type 2 Diabetes and Cholesterol Metabolism
We postulated that type 2 diabetes (T2D) predisposes patients to exocrine pancreatic diseases through (epi)genetic mechanisms. We explored the methylome (using MethylationEPIC arrays) of the exocrine pancreas in 141 donors, assessing the impact of T2D. An epigenome-wide association study of T2D identified hypermethylation in an enhancer of the pancreatic lipase–related protein 1 (PNLIPRP1) gene, associated with decreased PNLIPRP1 expression. PNLIPRP1 null variants (found in 191,000 participants in the UK Biobank) were associated with elevated glycemia and LDL cholesterol. Mendelian randomization using 2.5M SNP Omni arrays in 111 donors revealed that T2D was causal of PNLIPRP1 hypermethylation, which in turn was causal of LDL cholesterol. Additional AR42J rat exocrine cell analyses demonstrated that Pnliprp1 knockdown induced acinar-to-ductal metaplasia, a known prepancreatic cancer state, and increased cholesterol levels, reversible with statin. This (epi)genetic study suggests a role for PNLIPRP1 in human metabolism and exocrine pancreatic function, with potential implications for pancreatic diseases. Article Highlights
Authors
- Piero Marchetti (ORCID: https://orcid.org/0000-0003-4907-0635)
- François Pattou (ORCID: https://orcid.org/0000-0001-8388-3766)
- Philippe Froguel (ORCID: https://orcid.org/0000-0003-2972-0784)
- Carmela De Luca
- Amna Khamis (ORCID: https://orcid.org/0000-0003-1709-304X)
- Amélie Bonnefond (ORCID: https://orcid.org/0000-0001-9976-3005)
- Mara Suleiman (ORCID: https://orcid.org/0000-0002-2478-8782)
- Audrey Leloire
- Mickaël Canouil (ORCID: https://orcid.org/0000-0002-3396-4549)
- Vincent Pascat (ORCID: https://orcid.org/0000-0002-6227-8812)
- Sigurd Lenzen (ORCID: https://orcid.org/0000-0003-2125-8193)
- Lucas Maurin (ORCID: https://orcid.org/0009-0004-8607-4146)
- Lorella Marselli (ORCID: https://orcid.org/0000-0002-6698-2962)
- Souhila Amanzougarene
- Raphaël Boutry
- Lijiao Ning (ORCID: https://orcid.org/0000-0001-5958-3253)
- Mathilde Boissel (ORCID: https://orcid.org/0000-0001-5719-8749)
- Bénédicte Toussaint
- Julie Kerr‐Conte (ORCID: https://orcid.org/0000-0002-7590-1896)
- Mehdi Derhourhi (ORCID: https://orcid.org/0000-0001-5020-5379)
- Anne Jörns (ORCID: https://orcid.org/0000-0003-0176-972X)
- Justine Fernandes
Institutions
- University of Pisa (IT)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pasteur (FR)
- Université de Lille (FR)
- Institut Pasteur de Lille (FR)
- Medizinische Hochschule Hannover (DE)
- Genomics England (GB)
- European Genomic Institute for Diabetes (FR)
- Imperial College London (GB)
Publication Details
- Journal
- Diabetes
- Published
- 2024-08-13
- DOI
- https://doi.org/10.2337/db24-0215
- Citations
- 3
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- European Commission
- Agence Nationale de la Recherche
- Société Francophone du Diabète
- Conseil Régional Hauts-de-France
- HORIZON EUROPE Framework Programme
- European Research Council
- European Regional Development Fund
- CHIST-ERA