Section of Biochemistry, DIMES, University of Genova, 16132 Genova, Italy.
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Cells. 2022 Nov 28;11(23):3812. doi: 10.3390/cells11233812.
Boosting NAD levels are considered a promising means to promote healthy aging and ameliorate dysfunctional metabolism. The expression of CD38, the major NAD-consuming enzyme, is downregulated during thermogenesis in both brown and white adipose tissues (BAT and WAT). Moreover, BAT activation and WAT "browning" were enhanced in mice. In this study, the role of CD38 in the liver during thermogenesis was investigated, with the liver being the central organ controlling systemic energy metabolism. Wild-type mice and mice were exposed to cold temperatures, and levels of metabolites and enzymes were measured in the livers and plasma. During cold exposure, CD38 expression was downregulated in the liver, as in BAT and WAT, with a concomitant increase in NAD(H) and a marked decrease in NADPH levels. Glucose-6-phosphate dehydrogenase and the malic enzyme, along with enzymes in the glycolytic pathway, were downregulated, which is in line with glucose-6-P being re-directed towards glucose release. In mice, the cross-regulation between glycolysis and glucose release was lost, although this did not impair the glucose release from glycogen. Glycerol levels were decreased in the liver from animals upon cold exposure, suggesting that glyceroneogenesis, as gluconeogenesis, was not properly activated in the absence of CD38. SIRT3 activity, regulating mitochondrial metabolism, was enhanced by cold exposure, whereas its activity was already high at a warm temperature in mice and was not further increased by the cold. Notably, FGF21 and bile acid release was enhanced in the liver of mice, which might contribute to enhanced BAT activation in mice. These results demonstrate that CD38 inhibition can be suggested as a strategy to boost NAD and would not negatively affect hepatic functions during thermogenesis.
提高 NAD 水平被认为是促进健康衰老和改善功能障碍代谢的一种有前途的方法。在棕色和白色脂肪组织（BAT 和 WAT）的产热过程中，CD38 的表达（主要的 NAD 消耗酶）被下调。此外，在 小鼠中，BAT 的激活和 WAT 的“棕色化”增强。在这项研究中，研究了 CD38 在产热过程中在肝脏中的作用，肝脏是控制全身能量代谢的中心器官。野生型小鼠和 小鼠暴露于冷环境中，测量肝脏和血浆中的代谢物和酶水平。在冷暴露期间，与 BAT 和 WAT 一样，肝脏中 CD38 的表达下调，同时 NAD(H) 增加，NADPH 水平显著下降。葡萄糖-6-磷酸脱氢酶和苹果酸酶以及糖酵解途径中的酶下调，这与葡萄糖-6-磷酸被重新导向葡萄糖释放一致。在 小鼠中，尽管这并没有损害糖原释放的葡萄糖，但糖酵解和葡萄糖释放之间的交叉调节丧失了。冷暴露后， 小鼠肝脏中的甘油水平下降，表明甘油酮生成（如同糖异生）在没有 CD38 的情况下不能正常激活。调节线粒体代谢的 SIRT3 活性在冷暴露下增强，而在温暖温度下， 小鼠的 SIRT3 活性已经很高，并且不会因寒冷而进一步增加。值得注意的是， 小鼠肝脏中的 FGF21 和胆汁酸释放增强，这可能有助于增强 小鼠 BAT 的激活。这些结果表明，CD38 抑制可以作为提高 NAD 的策略，并且在产热过程中不会对肝脏功能产生负面影响。
