Stearoyl CoA Desaturase is a Gatekeeper That Protects Human Beta Cells Against Lipotoxicity and Maintains Their Identity

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2019 Dec 5

PMID 31796987

Citations 21

Authors

Masaya Oshima

Severine Pechberty

Lara Bellini

Sven O Gopel

Melanie Campana

Claude Rouch

Julien Dairou

Cristina Cosentino

Federica Fantuzzi

Sanna Toivonen

Piero Marchetti

Christophe Magnan

Miriam Cnop

Herve Le Stunff

Raphael Scharfmann

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: During the onset of type 2 diabetes, excessive dietary intake of saturated NEFA and fructose lead to impaired insulin production and secretion by insulin-producing pancreatic beta cells. The majority of data on the deleterious effects of lipids on functional beta cell mass were obtained either in vivo in rodent models or in vitro using rodent islets and beta cell lines. Translating data from rodent to human beta cells remains challenging. Here, we used the human beta cell line EndoC-βH1 and analysed its sensitivity to a lipotoxic and glucolipotoxic (high palmitate with or without high glucose) insult, as a way to model human beta cells in a type 2 diabetes environment.

Methods: EndoC-βH1 cells were exposed to palmitate after knockdown of genes related to saturated NEFA metabolism. We analysed whether and how palmitate induces apoptosis, stress and inflammation and modulates beta cell identity.

Results: EndoC-βH1 cells were insensitive to the deleterious effects of saturated NEFA (palmitate and stearate) unless stearoyl CoA desaturase (SCD) was silenced. SCD was abundantly expressed in EndoC-βH1 cells, as well as in human islets and human induced pluripotent stem cell-derived beta cells. SCD silencing induced markers of inflammation and endoplasmic reticulum stress and also IAPP mRNA. Treatment with the SCD products oleate or palmitoleate reversed inflammation and endoplasmic reticulum stress. Upon SCD knockdown, palmitate induced expression of dedifferentiation markers such as SOX9, MYC and HES1. Interestingly, SCD knockdown by itself disrupted beta cell identity with a decrease in mature beta cell markers INS, MAFA and SLC30A8 and decreased insulin content and glucose-stimulated insulin secretion.

Conclusions/interpretation: The present study delineates an important role for SCD in the protection against lipotoxicity and in the maintenance of human beta cell identity.

Data Availability: Microarray data and all experimental details that support the findings of this study have been deposited in in the GEO database with the GSE130208 accession code.

Citing Articles

High expression of stearoyl-coenzyme A desaturase in colorectal cancer oncogenic functions and its potential as a therapeutic target.

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PMID: 40061980 PMC: 11885988. DOI: 10.4240/wjgs.v17.i2.100237.

Gain of pancreatic beta cell-specific SCD1 improves glucose homeostasis by maintaining functional beta cell mass under metabolic stress.

Yin W, Zou S, Sha M, Sun L, Gong H, Xiong C Diabetologia. 2024; 68(3):629-645.

PMID: 39690249 DOI: 10.1007/s00125-024-06343-w.

A stearate-rich diet and oleate restriction directly inhibit tumor growth via the unfolded protein response.

Ogura J, Yamanoi K, Ishida K, Nakamura E, Ito S, Aoyama N Exp Mol Med. 2024; 56(12):2659-2672.

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Gojani E, Rai S, Norouzkhani F, Shujat S, Wang B, Li D Curr Issues Mol Biol. 2024; 46(7):7621-7667.

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Comparison of the effects of monounsaturated fatty acids and polyunsaturated fatty acids on the lipotoxicity of islets.

Liu W, Zhu M, Liu J, Su S, Zeng X, Fu F Front Endocrinol (Lausanne). 2024; 15:1368853.

PMID: 38501107 PMC: 10945794. DOI: 10.3389/fendo.2024.1368853.

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