TY - JOUR
T1 - Sirt1 counteracts decrease in membrane phospholipid unsaturation and diastolic dysfunction during saturated fatty acid overload
AU - Yamamoto, Tsunehisa
AU - Endo, Jin
AU - Kataoka, Masaharu
AU - Matsuhashi, Tomohiro
AU - Katsumata, Yoshinori
AU - Shirakawa, Kosuke
AU - Yoshida, Naohiro
AU - Isobe, Sarasa
AU - Moriyama, Hidenori
AU - Goto, Shinichi
AU - Yamashita, Kaoru
AU - Ohto-Nakanishi, Takayo
AU - Nakanishi, Hiroki
AU - Shimanaka, Yuta
AU - Kono, Nozomu
AU - Shinmura, Ken
AU - Arai, Hiroyuki
AU - Fukuda, Keiichi
AU - Sano, Motoaki
N1 - Funding Information:
This study was supported by JST PRESTO grants (2013–2015) and JSPS KAKENHI grants 15H04825 (2015–2017) and 15H01160 (2015–2016) (to Dr. Sano).
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/8
Y1 - 2019/8
N2 - Background: The fatty acid (FA)composition of membrane phospholipid reflects at least in part dietary fat composition. Saturated FA (SFA)suppress Sirt1 activity, while monounsaturated FA (MUFA)counteract this effect. Objective: We explored a role of Sirt1 in homeostatic control of the fatty acid composition of membrane phospholipid in the presence of SFA overload. Methods and results: Sirt1 deficiency in cardiomyocytes decreased the expression levels of liver X receptor (LXR)-target genes, particularly stearoyl-CoA desaturase-1 (Scd1), a rate-limiting enzyme in the cellular synthesis of MUFA from SFA, increased membrane SFA/MUFA ratio, and worsened left ventricular (LV)diastolic function in mice fed an SFA-rich high fat diet. In cultured cardiomyocytes, Sirt1 knockdown (KD)exacerbated the palmitate overload-induced increase in membrane SFA/MUFA ratio, which was associated with decrease in the expression of LXR-target genes, including Scd1. Forced overexpression of Scd1 in palmitate-overloaded Sirt1KD cardiomyocytes lowered the SFA/MUFA ratio. Nicotinamide mononucleotide (NMN)increased Sirt1 activity and Scd1 expression, thereby lowering membrane SFA/MUFA ratio in palmitate-overloaded cardiomyocytes. These effects of NMN were not observed for Scd1KD cardiomyocytes. LXRα/βKD exacerbated palmitate overload-induced increase in membrane SFA/MUFA ratio, while LXR agonist T0901317 alleviated it. NMN failed to rescue Scd1 protein expression and membrane SFA/MUFA ratio in palmitate-overloaded LXRα/βKD cardiomyocytes. The administration of NMN or T0901317 showed a dramatic reversal in membrane SFA/MUFA ratio and LV diastolic function in SFA-rich HFD-fed mice. Conclusion: Cardiac Sirt1 counteracted SFA overload-induced decrease in membrane phospholipid unsaturation and diastolic dysfunction via regulating LXR-mediated transcription of the Scd1 gene.
AB - Background: The fatty acid (FA)composition of membrane phospholipid reflects at least in part dietary fat composition. Saturated FA (SFA)suppress Sirt1 activity, while monounsaturated FA (MUFA)counteract this effect. Objective: We explored a role of Sirt1 in homeostatic control of the fatty acid composition of membrane phospholipid in the presence of SFA overload. Methods and results: Sirt1 deficiency in cardiomyocytes decreased the expression levels of liver X receptor (LXR)-target genes, particularly stearoyl-CoA desaturase-1 (Scd1), a rate-limiting enzyme in the cellular synthesis of MUFA from SFA, increased membrane SFA/MUFA ratio, and worsened left ventricular (LV)diastolic function in mice fed an SFA-rich high fat diet. In cultured cardiomyocytes, Sirt1 knockdown (KD)exacerbated the palmitate overload-induced increase in membrane SFA/MUFA ratio, which was associated with decrease in the expression of LXR-target genes, including Scd1. Forced overexpression of Scd1 in palmitate-overloaded Sirt1KD cardiomyocytes lowered the SFA/MUFA ratio. Nicotinamide mononucleotide (NMN)increased Sirt1 activity and Scd1 expression, thereby lowering membrane SFA/MUFA ratio in palmitate-overloaded cardiomyocytes. These effects of NMN were not observed for Scd1KD cardiomyocytes. LXRα/βKD exacerbated palmitate overload-induced increase in membrane SFA/MUFA ratio, while LXR agonist T0901317 alleviated it. NMN failed to rescue Scd1 protein expression and membrane SFA/MUFA ratio in palmitate-overloaded LXRα/βKD cardiomyocytes. The administration of NMN or T0901317 showed a dramatic reversal in membrane SFA/MUFA ratio and LV diastolic function in SFA-rich HFD-fed mice. Conclusion: Cardiac Sirt1 counteracted SFA overload-induced decrease in membrane phospholipid unsaturation and diastolic dysfunction via regulating LXR-mediated transcription of the Scd1 gene.
KW - Diastolic dysfunction
KW - Membrane fatty acid composition
KW - Saturated fatty acid
KW - Sirt1
KW - Stearoyl-CoA desaturase-1
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U2 - 10.1016/j.yjmcc.2019.05.019
DO - 10.1016/j.yjmcc.2019.05.019
M3 - Article
C2 - 31145942
AN - SCOPUS:85066303971
SN - 0022-2828
VL - 133
SP - 1
EP - 11
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -