Yiew Nicole K H, Deja Stanislaw, Ferguson Daniel, Cho Kevin, Jarasvaraparn Chaowapong, Jacome-Sosa Miriam, Lutkewitte Andrew J, Mukherjee Sandip, Fu Xiaorong, Singer Jason M, Patti Gary J, Burgess Shawn C, Finck Brian N
Department of Medicine, Center for Human Nutrition, Washington University in St. Louis, St. Louis, MO 63110, USA.
Center for Human Nutrition, University of Texas Southwestern, Dallas, TX 75390, USA.
iScience. 2023 Oct 12;26(11):108196. doi: 10.1016/j.isci.2023.108196. eCollection 2023 Nov 17.
The liver coordinates the systemic response to nutrient deprivation and availability by producing glucose from gluconeogenesis during fasting and synthesizing lipids via lipogenesis (DNL) when carbohydrates are abundant. Mitochondrial pyruvate metabolism is thought to play important roles in both gluconeogenesis and DNL. We examined the effects of hepatocyte-specific mitochondrial pyruvate carrier (MPC) deletion on the fasting-refeeding response. Rates of DNL during refeeding were impaired by hepatocyte MPC deletion, but this did not reduce intrahepatic lipid content. During fasting, glycerol is converted to glucose by two pathways; a direct cytosolic pathway and an indirect mitochondrial pathway requiring the MPC. Hepatocyte MPC deletion reduced the incorporation of C-glycerol into TCA cycle metabolites, but not into new glucose. Furthermore, suppression of glycerol and alanine metabolism did not affect glucose concentrations in fasted hepatocyte-specific MPC-deficient mice, suggesting multiple layers of redundancy in glycemic control in mice.
肝脏通过在禁食期间通过糖异生产生葡萄糖以及在碳水化合物丰富时通过脂肪生成（DNL）合成脂质来协调对营养缺乏和营养可利用性的全身反应。线粒体丙酮酸代谢被认为在糖异生和DNL中都起重要作用。我们研究了肝细胞特异性线粒体丙酮酸载体（MPC）缺失对禁食-再喂养反应的影响。肝细胞MPC缺失会损害再喂养期间的DNL速率，但这并未降低肝内脂质含量。在禁食期间，甘油通过两条途径转化为葡萄糖；一条直接的胞质途径和一条需要MPC的间接线粒体途径。肝细胞MPC缺失减少了C-甘油掺入三羧酸循环代谢物，但未减少掺入新葡萄糖。此外，抑制甘油和丙氨酸代谢并不影响禁食的肝细胞特异性MPC缺陷小鼠的血糖浓度，这表明小鼠血糖控制存在多层冗余。
