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. 2024 Nov 1;73(11):1908-1918.
doi: 10.2337/db24-0215.

PNLIPRP1 Hypermethylation in Exocrine Pancreas Links Type 2 Diabetes and Cholesterol Metabolism

Lucas Maurin  1   2 , Lorella Marselli  3 , Mathilde Boissel  1   2 , Lijiao Ning  1   2 , Raphael Boutry  1   2 , Justine Fernandes  1   2 , Mara Suleiman  3 , Carmela De Luca  3 , Audrey Leloire  1   2 , Vincent Pascat  1   2 , Bénédicte Toussaint  1   2 , Souhila Amanzougarene  1   2 , Mehdi Derhourhi  1   2 , Anne Jörns  4 , Sigurd Lenzen  4 , François Pattou  1 , Julie Kerr-Conte  5 , Mickaël Canouil  1 , Piero Marchetti  3 , Amélie Bonnefond  1   2   6 , Philippe Froguel  1   2   6 , Amna Khamis  1   2   6
Affiliations

PNLIPRP1 Hypermethylation in Exocrine Pancreas Links Type 2 Diabetes and Cholesterol Metabolism

Lucas Maurin et al. Diabetes. .

Abstract

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.

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