Palmitate reduces starvation-induced ER stress by inhibiting ER-phagy in hypothalamic cells

Yun Lim,Eun-Kyoung Kim,Seolsong Kim

doi:10.1186/s13041-021-00777-8

Yun Lim, Eun-Kyoung Kim + Show 1 more

Open Access

https://doi.org/10.1186/s13041-021-00777-8

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Abstract

Palmitate is a saturated fatty acid that is well known to induce endoplasmic reticulum (ER) stress and autophagy. A high-fat diet increases the palmitate level in the hypothalamus, the main region of the brain regulating energy metabolism. Interestingly, hypothalamic palmitate level is also increased under starvation, urging the study to distinguish the effects of elevated hypothalamic palmitate level under different nutrient conditions. Herein, we show that ER-phagy (ER-targeted selective autophagy) is required for progress of ER stress and that palmitate decreases ER stress by inhibiting ER-phagy in hypothalamic cells under starvation. Palmitate inhibited starvation-induced ER-phagy by increasing the level of B-cell lymphoma 2 (Bcl-2) protein, which inhibits autophagy initiation. These findings suggest that, unlike the induction of ER stress under nutrient-rich conditions, palmitate protects hypothalamic cells from starvation-induced stress by inhibiting ER-phagy.

Highlights

Consumption of high-fat diet (HFD) is one of the major factors leading to the development of obesity and related complications
Palmitate induces endoplasmic reticulum (ER) stress and autophagy at early time points but prolonged palmitate treatment impairs autophagy under nutrient‐rich conditions To examine the effect of palmitate on ER stress in the mouse hypothalamic cell line N41 under normal nutrient-rich conditions, we checked the activation of three unfolded protein response (UPR) sensor proteins, inositol-requiring transmembrane kinase/ endonuclease 1 (IRE1), pancreatic ER kinase (PERK), and activating transcription factor 6 (ATF6), following treatment with various concentrations of palmitate (Fig. 1a, b)
Palmitate treatment for 12 h increased the levels of both Phosphorylated PERK (p-PERK) (50 and 100 μM) and ATF6 (100 μM), while Phosphorylated IRE1 (p-IRE1) did not change (Fig. 1a, b)

Summary

Introduction

Consumption of high-fat diet (HFD) is one of the major factors leading to the development of obesity and related complications. The level of palmitate, a 16-carbon saturated fatty acid, is increased in the brain of both obese mice and humans [2, 3]. The hypothalamus is a brain region crucial for maintaining energy homeostasis by regulating food intake, energy expenditure, and the endocrine system in the Palmitate induces ER stress that activates the unfolded protein response (UPR) [12]. Stimuli such as aggregated proteins or unfolded proteins in the ER lumen provoke UPR to handle ER stress.

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