Department of Clinical Science, University of Bergen, Bergen, Norway.
Department of Biotechnology and Food Science, Faculty of Natural Sciences, NTNU Norwegian University of Science and Technology, N-7491 Trondheim, Norway.
Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Apr;1866(4):158887. doi: 10.1016/j.bbalip.2021.158887. Epub 2021 Jan 14.
Discovery of specific markers that reflect altered hepatic fatty acid oxidation could help to detect an individual's risk of fatty liver, type 2 diabetes and cardiovascular disease at an early stage. Lipid and protein metabolism are intimately linked, but our understanding of this crosstalk remains limited.
In male Wistar rats, we used synthetic fatty acid analogues (3-thia fatty acids) as a tool to induce hepatic fatty acid oxidation and mitochondrial biogenesis, to gain new insight into the link between fatty acid oxidation, amino acid metabolism and TCA cycle-related intermediate metabolites in liver and plasma.
Rats treated with 3-thia fatty acids had 3-fold higher hepatic, but not adipose and skeletal muscle, expression of the thioesterase 3-hydroxyisobutyryl-CoA hydrolase (Hibch), which controls the formation of 3-hydroxyisobutyrate (3-HIB) in the valine degradation pathway. Consequently, 3-thia fatty acid-stimulated hepatic fatty acid oxidation and ketogenesis was accompanied by decreased plasma 3-HIB and increased methylmalonic acid (MMA) concentrations further downstream in BCAA catabolism. The higher plasma MMA corresponded to higher MMA-CoA hydrolase activity and hepatic expression of GTP-specific succinyl-CoA synthase (Suclg2) and succinate dehydrogenase (Sdhb), and lower MMA-CoA mutase activity. Plasma 3-HIB correlated positively to plasma and hepatic concentrations of TAG, plasma total fatty acids, plasma NEFA and insulin/glucose ratio, while the reverse correlations were seen for MMA.
Our study provides new insight into TCA cycle-related metabolic changes associated with altered hepatic fatty acid flux, and identifies 3-HIB and MMA as novel circulating markers reflective of mitochondrial β-oxidation in male Wistar rats.
发现反映肝脂肪酸氧化改变的特异性标志物有助于在早期发现个体患脂肪肝、2 型糖尿病和心血管疾病的风险。脂质和蛋白质代谢密切相关，但我们对这种串扰的理解仍然有限。
在雄性 Wistar 大鼠中，我们使用合成脂肪酸类似物（3-硫代脂肪酸）作为工具，诱导肝脂肪酸氧化和线粒体生物发生，以深入了解肝和血浆中脂肪酸氧化、氨基酸代谢和 TCA 循环相关中间代谢物之间的联系。
用 3-硫代脂肪酸处理的大鼠肝组织中硫酯酶 3-羟基异丁酰辅酶 A 水解酶（Hibch）的表达增加了 3 倍，但脂肪组织和骨骼肌中没有增加，该酶控制支链氨基酸（BCAA）分解途径中 3-羟基异丁酸（3-HIB）的形成。因此，3-硫代脂肪酸刺激的肝脂肪酸氧化和酮体生成伴随着血浆 3-HIB 浓度降低和 BCAA 分解代谢中 downstream 的甲基丙二酸（MMA）浓度增加。较高的血浆 MMA 对应于较高的 MMA-辅酶 A 水解酶活性和肝 GTP 特异性琥珀酰辅酶 A 合成酶（Suclg2）和琥珀酸脱氢酶（Sdhb）表达，以及较低的 MMA-辅酶 A 变位酶活性。血浆 3-HIB 与血浆和肝 TAG、血浆总脂肪酸、血浆非酯化脂肪酸和胰岛素/葡萄糖比值呈正相关，而与 MMA 呈负相关。
本研究提供了有关与肝脂肪酸通量改变相关的 TCA 循环相关代谢变化的新见解，并确定 3-HIB 和 MMA 作为反映雄性 Wistar 大鼠线粒体β氧化的新型循环标志物。
