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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
虾米发布了新的文献求助10
刚刚
1秒前
Akim应助李芬采纳,获得10
1秒前
科研通AI2S应助Li采纳,获得10
2秒前
CipherSage应助范先生采纳,获得10
2秒前
lm发布了新的文献求助10
2秒前
情怀应助沉静丹寒采纳,获得30
2秒前
zhj完成签到 ,获得积分20
2秒前
朝颜发布了新的文献求助10
3秒前
3秒前
大方小白完成签到,获得积分10
4秒前
5秒前
LCR发布了新的文献求助10
5秒前
5秒前
5秒前
5秒前
WantoXi完成签到,获得积分10
6秒前
wbh完成签到,获得积分10
6秒前
er完成签到,获得积分20
7秒前
7秒前
关尔匕禾页完成签到,获得积分10
7秒前
hua应助尔尔采纳,获得10
8秒前
认真懿轩关注了科研通微信公众号
9秒前
pluto应助王子语采纳,获得10
9秒前
李健应助光能使者采纳,获得10
9秒前
9秒前
xiaolaohu发布了新的文献求助10
9秒前
10秒前
10秒前
11秒前
文耀海发布了新的文献求助10
11秒前
11秒前
科目三应助陈什么烨采纳,获得10
12秒前
12秒前
12秒前
斯文败类应助杜阳辉采纳,获得10
12秒前
13秒前
13秒前
大个应助周游采纳,获得10
13秒前
14秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3988827
求助须知:如何正确求助?哪些是违规求助? 3531183
关于积分的说明 11252671
捐赠科研通 3269809
什么是DOI,文献DOI怎么找? 1804780
邀请新用户注册赠送积分活动 881885
科研通“疑难数据库(出版商)”最低求助积分说明 809021