Pancreatic adenocarcinoma, chronic pancreatitis, and MODY-8 diabetes: is bile salt-dependent lipase (or carboxyl ester lipase) at the crossroads of pancreatic pathologies?

Abstract

Pancreatic adenocarcinomas and diabetes mellitus are responsible for the deaths of around two million people each year worldwide. Patients with chronic pancreatitis do not die directly of this disease, except where the pathology is hereditary. Much current literature supports the involvement of bile salt-dependent lipase (BSDL), also known as carboxyl ester lipase (CEL), in the pathophysiology of these pancreatic diseases. The purpose of this review is to shed light on connections between chronic pancreatitis, diabetes, and pancreatic adenocarcinomas by gaining an insight into BSDL and its variants. This enzyme is normally secreted by the exocrine pancreas, and is diverted within the intestinal lumen to participate in the hydrolysis of dietary lipids. However, BSDL is also expressed by other cells and tissues, where it participates in lipid homeostasis. Variants of BSDL resulting from germline and/or somatic mutations (nucleotide insertion/deletion or nonallelic homologous recombination) are expressed in the pancreas of patients with pancreatic pathologies such as chronic pancreatitis, MODY-8, and pancreatic adenocarcinomas. We discuss the possible link between the expression of BSDL variants and these dramatic pancreatic pathologies, putting forward the suggestion that BSDL and its variants are implicated in the cell lipid metabolism/reprogramming that leads to the dyslipidemia observed in chronic pancreatitis, MODY-8, and pancreatic adenocarcinomas. We also propose potential strategies for translation to therapeutic applications.

Keywords: bile salt-dependent lipase; carboxyl ester lipase; chronic pancreatitis; diabetes; pancreatic adenocarcinoma.

Figure 1. Schematic representation of the BSDL gene coding sequence

Numbered boxes represent each exon of the gene. Arrows show the sequence areas that code for specific structures or sites of the protein. The amino acids involved in the catalytic site of BSDL are indicated in blue. VNTR sequences encoded by exon 11 (blue box) are displayed as full amino acid sequences.

Figure 2. Schematic representations of human BSDL variants and associated pathologies

The sequences of exons 1 to 10 encoding the N-terminal domain of BSDL are represented in purple. VNTR sequences are in blue; each box represents a single VNTR. The sequences of the VNTR that are modified upon mutation (i.e., insertion, deletion), or recombination are colored in orange (MODY-8 diabetes), red (chronic pancreatitis), or dark purple (PAC), along with the corresponding C-terminal sequence of the protein.

Figure 3. Schematic representation of the putative link between pancreatic pathologies and the variants of BSDL

This shows the potential pathophysiological consequences of expression of human BSDL variants.

Figure 4. Tentative model to illustrate the involvement of the expression of BSDL/CEL variants and that of wild-type BSDL/CEL bearing post-translational modifications in pancreatic diseases

Note that post-translational modifications of BSDL variants may also be affected by the pathophysiological status of exocrine cell. In red characters are putative mechanisms impacting the pathophysiological status of exocrine or endocrine pancreatic cells. Core 2, β (1-6) N-acetylglucosaminyltransferase; Fuc-T3 and Fuc-T7, Fucosyltransferase 3 and 7; UPR, unfolded protein response.