Encarnacion Jasmine, Smith Danielle M, Choi Joseph, Scafidi Joseph, Wolfgang Michael J
Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Biol Chem. 2025 May;301(5):108468. doi: 10.1016/j.jbc.2025.108468. Epub 2025 Mar 28.
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 KOs 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 KO 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.
在不断变化的代谢应激源下，肝脏在维持全身糖脂稳态方面发挥着重要作用。代谢失调可导致影响全身生理机能的适应性和非适应性变化。在此，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，在肝脏特异性敲除肉碱棕榈酰转移酶2和丙酮酸羧化酶的小鼠中上调。我们发现禁食、高脂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）会随之增加。肝脏特异性过表达Atf3会导致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，我们构建了肝脏特异性Atf3、Cpt2双敲除小鼠。这些实验证明了Atf3在诱导ApoA4 mRNA、ApoA4蛋白和血清甘油三酯方面的需求，且这些需求也是性别依赖的。这些实验揭示了肝脏Atf3和ApoA4在体内对代谢应激的反应中的作用。
