Sirt1 counteracts decrease in membrane phospholipid unsaturation and diastolic dysfunction during saturated fatty acid overload

J Mol Cell Cardiol. 2019 Aug:133:1-11. doi: 10.1016/j.yjmcc.2019.05.019. Epub 2019 May 27.

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.

Keywords: Diastolic dysfunction; Membrane fatty acid composition; Saturated fatty acid; Sirt1; Stearoyl-CoA desaturase-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Diastole*
  • Diet, High-Fat
  • Disease Models, Animal
  • Disease Susceptibility
  • Fatty Acids / metabolism*
  • Fatty Acids, Monounsaturated / metabolism*
  • Lipid Metabolism
  • Liver X Receptors / agonists
  • Liver X Receptors / metabolism
  • Membrane Lipids / metabolism*
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac / metabolism
  • Phospholipids / metabolism*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Ventricular Dysfunction / etiology
  • Ventricular Dysfunction / metabolism*

Substances

  • Fatty Acids
  • Fatty Acids, Monounsaturated
  • Liver X Receptors
  • Membrane Lipids
  • Phospholipids
  • Sirtuin 1