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Published on: February 2, 2019
Sirt1 mediates the effects of a short-term high-fat diet on the heart
Joan Villarroya1, Ibon Redondo-Angulo2, Roser Iglesias2
1Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición, 08028, Barcelona, Spain; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Abstract:
High-fat diet leads to development of cardiac dysfunction through molecular mechanisms poorly known. The aim of this study is to elucidate the early events in cardiac dysfunction caused by a high-fat diet, before massive alterations due to obesity and indirect mechanisms of heart damage take place. Moreover, we analyzed the role of Sirt1, a major mediator of cardiac gene regulation, in these effects. Short-term high-fat feeding (5 weeks) caused a similar mild increase in body weight and triglyceridaemia in wild-type (wt) and Sirt1(+/-) mice. The high-fat diet suppressed the expression of lipid catabolism (PPARα target) gene expression in the hearts of wt mice, but not Sirt1(+/-) mice. Pro-inflammatory genes were induced and estrogen-related receptor-alpha (ERRα) target genes was suppressed in the hearts of wt fed the high-fat diet, but not in Sirt1(+/-) mice. We found the formation of a complex between PPARα and Sirt1 in wt mice under high-fat diet conditions which might account for suppression of the ERRα pathway. Sirt1 haploinsufficiency impairs the formation of this complex and promotes the binding of PPARα to the p65 subunit of NF-κB, thereby mediating inhibition of pro-inflammatory pathways and induction of PPARα target genes. Short-term high-fat diet causes metabolic and inflammatory alterations in heart, and Sirt1 is critical for mediating these cardiac alterations. The capacity of Sirt1 to interact with transcriptional regulators such as NF-κB and PPARα appears to be involved in the cardiac responsiveness to a high-fat diet.
Insights
A high-fat diet triggers early cardiac dysfunction by altering gene expression. Sirt1 protein is crucial, as its deficiency protects the heart from these diet-induced metabolic and inflammatory changes.
Area of Science:
- Cardiovascular Biology
- Molecular Metabolism
- Nutritional Science
Background:
- High-fat diets (HFD) induce cardiac dysfunction via poorly understood molecular pathways.
- Early cardiac alterations precede obesity-related damage, highlighting critical molecular events.
- Sirtuin 1 (Sirt1) is a key regulator of cardiac gene expression, implicated in metabolic adaptation.
Purpose of the Study:
- Elucidate early molecular events in high-fat diet-induced cardiac dysfunction.
- Investigate the role of Sirt1 in mediating these diet-induced cardiac alterations.
- Analyze the interaction of Sirt1 with key transcription factors in response to HFD.
Main Methods:
- Short-term high-fat diet feeding (5 weeks) in wild-type and Sirt1(+/-) mice.
- Analysis of cardiac gene expression, including lipid catabolism and inflammatory markers.
- Investigation of protein-protein interactions between Sirt1, PPARα, and NF-κB.
Main Results:
- HFD suppressed lipid catabolism and ERRα target genes in wild-type hearts but not in Sirt1(+/-) hearts.
- Sirt1 formed a complex with PPARα in HFD-fed wild-type mice, suppressing the ERRα pathway.
- Sirt1 haploinsufficiency prevented this complex, promoting PPARα-NF-κB binding and mitigating pro-inflammatory pathways.
Conclusions:
- Short-term high-fat diet induces cardiac metabolic and inflammatory changes.
- Sirt1 is critical in mediating these diet-induced cardiac alterations.
- Sirt1's interaction with NF-κB and PPARα influences cardiac response to high-fat diets.
