Activating Transcription Factor 3 regulates hepatic Apolipoprotein A4 upon metabolic stress.

IF 4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jasmine Encarnacion, Danielle M Smith, Joseph Choi, Joseph Scafidi, Michael J Wolfgang
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引用次数: 0

Abstract

The liver plays essential roles in maintaining systemic glucolipid homeostasis under ever changing metabolic stressors. Metabolic dysregulation can lead to both adaptive and maladaptive changes that impact systemic physiology. Here we examined disparate genetic and environmental metabolic stressors and identified Apolipoprotein A4 (ApoA4) as a circulating protein upregulated in liver-specific knockouts for Carnitine Palmitoyltransferase 2 and Pyruvate Carboxylase. We found this upregulation to be exacerbated by fasting and high fat or ketogenic diets. Unique among these models was a concomitant increase in Activating Transcription Factor 3 (Atf3). Liver-specific overexpression of Atf3 resulted in increased ApoA4 expression in a sex-dependent manner. To understand the requirement of Atf3 to metabolic stress, we generated liver-specific Atf3, Cpt2 double knockout mice. These experiments demonstrated the requirement for Atf3 in the induction of ApoA4 mRNA, ApoA4 protein, and serum triglycerides that were also sex dependent. These experiments reveal the roles of hepatic Atf3 and ApoA4 in response to metabolic stress in vivo.

激活转录因子3在代谢应激下调节肝脏载脂蛋白A4。
在不断变化的代谢应激源下,肝脏在维持全身糖脂稳态中起着至关重要的作用。代谢失调可导致影响全身生理的适应性和非适应性变化。在这里,我们研究了不同的遗传和环境代谢应激源,并确定载脂蛋白A4 (ApoA4)是一种循环蛋白,在肉毒碱棕榈酰基转移酶2和丙酮酸羧化酶的肝脏特异性敲除中上调。我们发现,禁食、高脂肪或生酮饮食会加剧这种上调。在这些模型中,独特的是激活转录因子3 (Atf3)的增加。肝脏特异性过表达Atf3导致ApoA4表达以性别依赖的方式增加。为了了解Atf3对代谢应激的需求,我们制造了肝脏特异性Atf3、Cpt2双敲除小鼠。这些实验表明,Atf3在诱导ApoA4 mRNA、ApoA4蛋白和血清甘油三酯方面也是性别依赖的。这些实验揭示了肝脏Atf3和ApoA4在体内代谢应激反应中的作用。
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来源期刊
Journal of Biological Chemistry
Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry
自引率
4.20%
发文量
1233
期刊介绍: The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.
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