Abstract 16726: High Fat Diet Upregulates Il-6 in the Heart Through Pparα
Obesity is a risk factor for diastolic heart failure, but the molecular mechanism by which obesity promotes diastolic dysfunction is not well understood. Obesity induces cardiac remodeling through upregulation of inflammatory cytokines. PPARα is a nuclear receptor activated by endogenous fatty acid ligands and controls genes involved in fatty acid metabolism and inflammation. However, the role of PPARα in the pathological development of diastolic heart failure and inflammatory cytokine expression in obesity is unknown. We hypothesize that PPARα contributes to the pathogenesis of diastolic heart failure by controlling cytokine production. Three months of high fat diet (HFD, 60% kcal% fat) consumption induced diastolic dysfunction in wild type (WT) mice, as evidenced by an increased end-diastolic pressure (EDP (mmHg): WT normal diet (ND): 7.4; WT HFD: 14.4, p<0.05) and EDP-volume relationship (EDPVR: WT ND: 0.07; WT HFD: 0.12, p<0.05), indices of diastolic dysfunction. The HFD-induced diastolic dysfunction was attenuated in PPARα knockout (PPARαKO) mice (EDP: PPARαKO ND: 7.5; PPARαKO HFD: 7.5*, p<0.05 vs. WT HFD, EDPVR: PPARαKO ND: 0.07; PPARαKO HFD: 0.08*, p<0.05 vs. WT HFD). HFD-induced systolic dysfunction was not observed in either WT or PPARαKO mice. HFD-induced cardiac fibrosis was attenuated in PPARαKO mice (relative PAS staining area: WT ND: 1; WT HFD: 2.4; PPARαKO ND: 0.7; PPARαKO HFD: 1.2*, p<0.05). Biochemical assays and immunohistological analyses showed that upregulation of interleukin-6 (IL-6), an inflammatory cytokine, was observed in WT hearts in response to HFD, but was attenuated in PPARαKO mice (relative IL-6 mRNA: WT HFD: 1.75, PPARαKO HFD: 0.85*, p<0.05). In cultured cardiomyocytes (CMs), overexpression of PPARα activated transcription of a reporter gene driven by the IL-6 promoter (3.1 fold, p<0.05). Activation of the IL-6 promoter by palmitic acid (PA), a fatty acid, was inhibited by PPARαΔAF2, a dominant-negative form of PPARα (relative reporter activity: control PA: 3.1; PPARαΔAF2 PA: 1.2, p<0.05). These results suggest that PPARα contributes to the pathogenesis of diastolic heart failure in response to HFD consumption and that PPARα mediates upregulation of inflammatory cytokines, including IL-6, in CMs.
Author Disclosures: S. Oka: None. A. Shirakabe: None. S. Bhat: None. P. Zhai: None. B. Magrys: None. M. Nakamura: None. J. Sadoshima: None.
- © 2016 by American Heart Association, Inc.