The Role of Sirtuin 1 in Palmitic Acid-Induced Endoplasmic Reticulum Stress in Cardiac Myoblasts.

Hsiang-Yu Yang,Pei-Ling Yu,Yen-Nien Huo,Chien-Sung Tsai,Shih-Ming Huang,Shih-Che Hsu,Chih-Yuan Lin,Pei-Zhen Lin,Jhao-Ying Chen

doi:10.3390/life12020182

Abstract

Background: Lipotoxicity causes endoplasmic reticulum (ER) stress, leading to cell apoptosis. Sirtuin 1 (Sirt1) regulates gene transcription and cellular metabolism. In this study, we investigated the role of Sirt1 in palmitate-induced ER stress. Methods: Both H9c2 myoblasts and heart-specific Sirt1 knockout mice fed a palmitate-enriched high-fat diet were used. Results: The high-fat diet induced C/EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4) expression in both Sirt1 knockout mice and controls. The Sirt1 knockout mice showed higher CHOP and ATF4 expression compared to those in the control. Palmitic acid (PA) induced ATF4 and CHOP expression in H9c2 cells. PA-treated H9c2 cells showed decreased cytosolic NAD+/NADH alongside reduced Sirt1′s activity. The H9c2 cells showed increased ATF4 and CHOP expression when transfected with plasmid encoding dominant negative mutant Sirt1. Sirt1 activator SRT1720 did not affect CHOP and ATF4 expression. Although SRT1720 enhanced the nuclear translocation of ATF4, the extent of the binding of ATF4 to the CHOP promoter did not increase in PA treated-H9c2 cells. Conclusion: PA-induced ER stress is mediated through the upregulation of ATF4 and CHOP. Cytosolic NAD+ concentration is diminished by PA-induced ER stress, leading to decreased Sirt1 activity. The Sirt1 activator SRT1720 promotes the nuclear translocation of ATF4 in PA-treated H9c2 cells.

Highlights

Cardiac lipotoxicity, featuring toxic lipid accumulation in the heart, plays a pathological role in the development of obesity induced cardiovascular diseases [1]
C/EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4) protein levels and mRNA expression were higher in the control mice fed with the high-fat diet (HFD) compared to those fed the standard diet (SD) (Figure 1A–C)
We examined whether the cellular NAD+/NADH ratio was affected, which may be responsible for the reduced deacetylating activity of Sirtuin 1 (Sirt1), under Palmitic acid (PA)-induced endoplasmic reticulum (ER) stress

Summary

Introduction

Cardiac lipotoxicity, featuring toxic lipid accumulation in the heart, plays a pathological role in the development of obesity induced cardiovascular diseases [1]. In the apoptosis pathways, activating transcription factor 4 (ATF4) plays a crucial role because it drives the transcription of several apoptosis genes, including a proapoptotic one, C/EBP homologous protein (CHOP), known as DNA damage–inducible transcript 3 protein. Results: The high-fat diet induced C/EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4) expression in both Sirt knockout mice and controls. The Sirt knockout mice showed higher CHOP and ATF4 expression compared to those in the control. Palmitic acid (PA) induced ATF4 and CHOP expression in H9c2 cells. Cytosolic NAD+ concentration is diminished by PA-induced ER stress, leading to decreased Sirt activity. The Sirt activator SRT1720 promotes the nuclear translocation of ATF4 in PA-treated H9c2 cells

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