TY - JOUR

T1 - The monounsaturated fatty acid oleate is the major physiological toxic free fatty acid for human beta cells

AU - Plötz, T

AU - Krümmel, B

AU - Laporte, A

AU - Pingitore, A

AU - Persaud, S J

AU - Jörns, A

AU - Elsner, M

AU - Mehmeti, I

AU - Lenzen, S

N1 - Funding information: This work was supported by the European Union (Collaborative Project BetaBAT in the Framework Programme 7, grant agreement 277713). A.L. is a PhD student within the Research Training Group (GRK) 1947 BiOx of the German Research Council at the University of Greifswald. We are grateful to Maren Böger and Martin Wirth for their skilful technical assistance, and to Dr Guo Cai Huang for isolation of the human islets used in this study.

PY - 2017/12/21

Y1 - 2017/12/21

N2 - Free fatty acids (FFAs) can cause glucose intolerance and diabetes. Lipotoxicity to the pancreatic beta cells is considered to be a major underlying cause for this phenomenon. The aim of this study was to analyse the toxicity profile of FFAs in the human EndoC-βH1 beta-cell line and to compare the results with isolated rat and human islets with special reference to the physiologically most prevalent FFAs palmitic acid (PA) and oleic acid (OA). Toxicity after a 2-day incubation with the different FFAs was analysed by the caspase-3 assay and confirmed by the propidium iodide and annexin V staining tests. The long-chain saturated PA (C16:0) and the monounsaturated OA (C18:1) were both toxic to human EndoC-βH1 beta cells and pseudoislets, as well as to rat islets, and, as confirmed in a pilot experiment, also to human islets. Furthermore, OA provided no protection against the toxicity of PA. Likewise, elaidic acid (EA, the trans isomer of OA; trans-OA) was significantly toxic, in contrast to the non-metabolisable analogues methylated PA (MePA) and methylated OA (MeOA). Fatty acids with a chain length  < C16 were not toxic in EndoC-βH1 beta cells. Caspase-3 was also activated by linoleic acid (LA)(C18:2) but not by γ-linolenic acid (γ-LNA)(C18:3). Overall, only long-chain FFAs with chain lengths  > C14, which generate hydrogen peroxide in the peroxisomal beta-oxidation, were toxic. This conclusion is also supported by the toxicity of the branched-chain FFA pristanic acid, which is exclusively metabolised in the peroxisomal beta-oxidation. The lack of a protective effect of the monounsaturated fatty acid OA has important consequences for a beta-cell protective lipid composition of a diet. A cardioprotective diet with a high OA content does not fulfil this requirement.

AB - Free fatty acids (FFAs) can cause glucose intolerance and diabetes. Lipotoxicity to the pancreatic beta cells is considered to be a major underlying cause for this phenomenon. The aim of this study was to analyse the toxicity profile of FFAs in the human EndoC-βH1 beta-cell line and to compare the results with isolated rat and human islets with special reference to the physiologically most prevalent FFAs palmitic acid (PA) and oleic acid (OA). Toxicity after a 2-day incubation with the different FFAs was analysed by the caspase-3 assay and confirmed by the propidium iodide and annexin V staining tests. The long-chain saturated PA (C16:0) and the monounsaturated OA (C18:1) were both toxic to human EndoC-βH1 beta cells and pseudoislets, as well as to rat islets, and, as confirmed in a pilot experiment, also to human islets. Furthermore, OA provided no protection against the toxicity of PA. Likewise, elaidic acid (EA, the trans isomer of OA; trans-OA) was significantly toxic, in contrast to the non-metabolisable analogues methylated PA (MePA) and methylated OA (MeOA). Fatty acids with a chain length  < C16 were not toxic in EndoC-βH1 beta cells. Caspase-3 was also activated by linoleic acid (LA)(C18:2) but not by γ-linolenic acid (γ-LNA)(C18:3). Overall, only long-chain FFAs with chain lengths  > C14, which generate hydrogen peroxide in the peroxisomal beta-oxidation, were toxic. This conclusion is also supported by the toxicity of the branched-chain FFA pristanic acid, which is exclusively metabolised in the peroxisomal beta-oxidation. The lack of a protective effect of the monounsaturated fatty acid OA has important consequences for a beta-cell protective lipid composition of a diet. A cardioprotective diet with a high OA content does not fulfil this requirement.

KW - Animals

KW - Caspase 3/metabolism

KW - Cell Line

KW - Fatty Acids, Monounsaturated/toxicity

KW - Humans

KW - Insulin-Secreting Cells/drug effects

KW - Oleic Acid/toxicity

KW - Palmitic Acid/toxicity

KW - Rats

KW - Rats, Inbred Lew

UR - http://www.scopus.com/inward/record.url?scp=85042372415&partnerID=8YFLogxK

U2 - 10.1038/s41387-017-0005-x

DO - 10.1038/s41387-017-0005-x

M3 - Article

C2 - 29269872

VL - 7

SP - 305

JO - Nutrition & Diabetes

JF - Nutrition & Diabetes

SN - 2044-4052

IS - 12

M1 - 305

ER -