10/9/2020 (Week 5)

 

Bile salt activated lipase

Cameron Siqueiros

Glendale Community College

 

Protein – P19835 (Bile salt-activated lipase)

 

Description - Bile salt-activated lipase is a major triglyceride, cholesterol ester and vitamin ester hydrolytic enzyme contained within pancreatic and lactating mammary gland secretions. It requires bile salts for activation. The biological process of bile salt activated lipase is known as lipid metabolic process.

 

Molecular function – hydrolase activity acting on ester bonds.

 

Function – to catalyze the hydrolysis of a wide range of substrates including cholesteryl esters, phospholipids, lysopholipids, di-acylglycerols, tri-acylglycerols, and fatty acid esters of hydroxy fatty acids or (FAHFAS). Preferentially hydrolyzes FAHFAs with the ester bond further away from the carboxylate. Unsaturated FAHFAs are hydrolyzed quicker than saturated FAHFA. Plays an important role in complete digestion of dietary lipids and their intestinal absorption of fat-soluble vitamins.

 

Diseases – Maturity-onset diabetes of the young 8 with exocrine dysfunction (MODY8). An autosomal dormant form of diabetes characterized by the primary defect in insulin secretion, exocrine pancreatic dysfunction, altered pancreatic morphology, recurrent abdominal pain, and fecal elastase deficiency. Occurs in people less than 25 years of age. Single base deletions in the VNTR-region results in frame shift and protein truncation have been identified as disease-causing variants in MODY8 families.

 

Structure – This sequence has 753 amino acids and molecular weight of 79322 Da

 

I decided to list all the information that was given on the European database ebi.ac.uk and based on the information in comparison to my previous look at uniprot.org the information is identical on almost every description of Bile salt-activated lipase. I didn’t notice any discrepancies and the information given on the European database also linked to uniprot.org for reference as well. Therefore, I think it’s safe to safe the information is valid in the European database as well. Many of the sources were direct links to uniprot.org or just identical information.

 

I began searching for P19835, Bile salt-activated lipase, BAL, Bile salt-simulated lipase, BSSL, Bucelipase and got no results for any gene-disease associations. I used these names from uniprot.org from the names and taxonomy tab under alternative names and finally I got gene-disease association results from the name carboxyl ester lipase. I then went under open target gene-disease associations and my top 3 results came back with.

 

CEL – Inborn errors of metabolism

Overall association score 1.0

MODY – “Pancreatic adenocarcinoma, chronic pancreatitis, and MODY-8 diabetes is bile salt-dependent lipase (or carboxyl ester lipase) at the crossroads of pancreatic pathologies” – Lombardo Dominique, Silvy Francoise, Isabelle Crenon et al. – 21 Dec 2017.

 

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.

 

 

CEL – Rare genetic endocrine disease

Overall association score 1.0

MODY – “Absence of diabetes and pancreatic exocrine dysfunction in a transgenic model of carboxyl-ester lipase-MODY (maturity-onset diabetes of the young)” – Helge Raeder, Mette Vesterhus, Abdelfattah El Ouaamari et al. – 01 Apr 2013.

 

Abstract - CEL-MODY is a monogenic form of diabetes with exocrine pancreatic insufficiency caused by mutations in CARBOXYL-ESTER LIPASE (CEL). The pathogenic processes underlying CEL-MODY are poorly understood, and the global knockout mouse model of the CEL gene (CELKO) did not recapitulate the disease. We therefore aimed to create and phenotype a mouse model specifically over-expressing mutated CEL in the pancreas. We established a monotransgenic floxed (flanking LOX sequences) mouse line carrying the human CEL mutation c.1686delT and crossed it with an elastase-Cre mouse to derive a bitransgenic mouse line with pancreas-specific over-expression of CEL carrying this disease-associated mutation (TgCEL). Following confirmation of murine pancreatic expression of the human transgene by real-time quantitative PCR, we phenotyped the mouse model fed a normal chow and compared it with mice fed a 60% high fat diet (HFD) as well as the effects of short-term and long-term cerulein exposure. Pancreatic exocrine function was normal in TgCEL mice on normal chow as assessed by serum lipid and lipid-soluble vitamin levels, fecal elastase and fecal fat absorption, and the normoglycemic mice exhibited normal pancreatic morphology. On 60% HFD, the mice gained weight to the same extent as controls, had normal pancreatic exocrine function and comparable glucose tolerance even after resuming normal diet and follow up to 22 months of age. The cerulein-exposed TgCEL mice gained weight and remained glucose tolerant, and there were no detectable mutation-specific differences in serum amylase, islet hormones or the extent of pancreatic tissue inflammation. In this murine model of human CEL-MODY diabetes, we did not detect mutation-specific endocrine or exocrine pancreatic phenotypes, in response to altered diets or exposure to cerulein.

 

CEL – metabolic disease

Overall association score 1.0

Obesity – “Inhibitory effects of various solvent extracts from Rhamnus frangula leaves on some inflammatory and metabolic enzymes” – Abir Ben Bacha, Ikram Jemel, Ramesa Shafi Bhat et al. – 29 Oct 2018.

 

Abstract - Many enzymes are involved in numerous pathologies which are related to metabolic reactions and inflammatory diseases such as pancreatic lipase, α-amylase, α-glucosidase and xanthine oxidase and secreted phospholipases A2 (Group IIA, V and X), respectively. Therefore, inhibiting these enzymes offer the potential to block production of more inflammatory substances and decrease the risk factors for cardiovascular diseases. The purpose of this study was to investigate some potent, bioavailable and selective inhibitors of some catalytic proteins implicated to metabolic syndrome and their antioxidant effects from various solvent extracts of R. frangula leaves. The anti-inflammatory, obesity, diabetes and XO potentials were evaluated through analyses of inhibition activities of corresponding metabolites. The water extract exhibited an important inhibitory effect on human, dromedary and stingray sPLA2-G IIA achieved an IC50 of 0.16±0.06, 0.19±0.05 and 0.07±0.01 mg/mL, respectively. Likewise, the same fraction demonstrated the highest pancreatic lipase inhibitory activity using two different substrates. Indeed, 50% of dromedary pancreatic lipase inhibition was demonstrated for 5 min and 15 min using olive oil and TC4 substrates, respectively. Besides, it was established that methanolic extract had more effective inhibitory lipase activity than ORLISTAT used as a specific inhibitor of gastric, pancreatic and carboxyl ester lipase for treating obesity, with an IC50 of 5.51±0.27 and 91.46±2.3 µg/mL, respectively. In the case of α-amylase, α-glucosidase and xanthine oxidase, the crude methanolic extract showed a potential inhibitory effect with an IC50 of 45±3.45, 3±0.15 and 27±1.71 µg/mL, respectively. Conclusively, R. frangula leaves extracts showed a potential value of some sPLA2, some metabolic enzymes and XO inhibitors as anti-inflammatory and metabolic syndrome drugs.

 

Citations

www.ebi.ac.uk/. (n.d.). Retrieved October 19, 2020, from https://www.ebi.ac.uk/ebisearch/s4/summary/molecular?tab=protein

 

Ben Bacha A, Jemel I, Bhat RS, Onizi MA. Inhibitory effects of various solvent extracts from Rhamnus frangula leaves on some inflammatory and metabolic enzymes. Cellular and Molecular Biology (Noisy-le-Grand, France). 2018 Oct;64(13):55-62.

 

Lombardo D, Silvy F, Crenon I, et al. Pancreatic adenocarcinoma, chronic pancreatitis, and MODY-8 diabetes: is bile salt-dependent lipase (or carboxyl ester lipase) at the crossroads of pancreatic pathologies? Oncotarget. 2018 Feb;9(15):12513-12533. DOI: 10.18632/oncotarget.23619.

 

Ræder H, Vesterhus M, El Ouaamari A, et al. Absence of diabetes and pancreatic exocrine dysfunction in a transgenic model of carboxyl-ester lipase-MODY (maturity-onset diabetes of the young). Plos one. 2013 ;8(4):e60229. DOI: 10.1371/journal.pone.0060229.