Sirt1 counteracts decrease in membrane phospholipid unsaturation and diastolic dysfunction during saturated fatty acid overload. (August 2019)

• Record Type: Journal Article
• Authors: Yamamoto, Tsunehisa; Endo, Jin; Kataoka, Masaharu; Matsuhashi, Tomohiro; Katsumata, Yoshinori; Shirakawa, Kohsuke; Yoshida, Naohiro; Isobe, Sarasa; Moriyama, Hidenori; Goto, Shinichi; Yamashita, Kaoru; Ohto-Nakanishi, Takayo; Nakanishi, Hiroki; Shimanaka, Yuta; Kono, Nozomu; Shinmura, Ken; Arai, Hiroyuki; Fukuda, Keiichi; Sano, Motoaki
• Is Part Of: Journal of molecular and cellular cardiology. Volume 133(2019)
• Page Start: 1
• Page End: 11
• Publication Date: 2019-08
• Subjects: Sirt1 -- Stearoyl-CoA desaturase-1 -- Membrane fatty acid composition -- Saturated fatty acid -- Diastolic dysfunction; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2019.05.019
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: 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. Graphical abstract: Unlabelled Image Highlights: SFA-rich HFD increased membrane SFA/MUFA ratio, leading to diastolic dysfunction. SFA-rich HFD suppressed protein expression levels of Sirt1. Sirt1 deficiency decreased the expression of LXR-target genes, particularly Scd1. Sirt1 deficiency worsen SFA overload-induced increase in membrane SFA/MUFA ratio. NMN brings a dramatic reversal in membrane SFA/MUFA ratio and diastolic dysfunction.