Afterload-induced Decreases in Fatty Acid Oxidation Develop Independently of Increased Glucose Utilization

β氧化 后负荷 脂肪酸 化学 业务 内科学 货币经济学 内分泌学 生物化学 经济 生物 医学 血流动力学
作者
Hande C. Piristine,Herman I. May,Nan Jiang,Daniel Daou,Francisco Olivares-Silva,Abdallah Elnwasany,Pamela A. Szweda,Luke I. Szweda,Caroline Kinter,Michael Kinter,Gaurav Sharma,Xiao-Dong Wen,Craig R. Malloy,Michael E. Jessen,Thomas G. Gillette,Joseph A. Hill
标识
DOI:10.1101/2024.09.17.613531
摘要

ABSTRACT Background Metabolic substrate utilization in HFpEF (heart failure with preserved ejection fraction), the leading cause of heart failure worldwide, is pivotal to syndrome pathogenesis and yet remains ill defined. Under resting conditions, oxidation of free fatty acids (FFA) is the predominant energy source of the heart, supporting its unremitting contractile activity. In the context of disease-related stress, however, a shift toward greater reliance on glucose occurs. In the setting of obesity or diabetes, major contributors to HFpEF pathophysiology, the shift in metabolic substrate use toward glucose is impaired, sometimes attributed to the lower oxygen requirement of glucose oxidation versus fat metabolism. This notion, however, has never been tested conclusively. Furthermore, whereas oxygen demand increases in the setting of increased afterload, myocardial oxygen availability remains adequate for fatty acid oxidation (FAO). Therefore, a “preference” for glucose has been proposed. Methods and Results Pyruvate dehydrogenase complex (PDC) is the rate-limiting enzyme linking glycolysis to the TCA cycle. As PDK4 (PDC kinase 4) is up-regulated in HFpEF, we over-expressed PDK4 in cardiomyocytes, ensuring that PDC is phosphorylated and thereby inhibited. This leads to diminished use of pyruvate as energy substrate, mimicking the decline in glucose oxidation in HFpEF. Importantly, distinct from HFpEF-associated obesity, this model positioned us to abrogate the load-induced shift to glucose utilization in the absence of systemic high fat conditions. As expected, PDK4 transgenic mice manifested normal cardiac performance at baseline. However, they manifested a rapid and severe decline in contractile performance when challenged with modest increases in afterload triggered either by L-NAME or surgical transverse aortic constriction (TAC). This decline in function was not accompanied by an exacerbation of the myocardial hypertrophic growth response. Surprisingly, metabolic flux analysis revealed that, after TAC, fractional FAO decreased, even when glucose/pyruvate utilization was clamped at very low levels. Additionally, proteins involved in the transport and oxidation of FFA were paradoxically downregulated after TAC regardless of genotype. Conclusions These data demonstrate that cardiomyocytes in a setting in which glucose utilization is robustly diminished and prevented from increasing do not compensate for the deficit in glucose utilization by up-regulating FFA use.
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