CD38 downregulation modulates NAD+ and NADP(H) levels in thermogenic adipose tissues

Benzi, Andrea; Sturla, Laura; Heine, Markus; Fischer, Alexander W.; Spinelli, Sonia; Magnone, Mirko; Sociali, Giovanna; Parodi, Alessia; Fenoglio, Daniela; Emionite, Laura; Koch‐Nolte, Friedrich; Mittrücker, Hans Willi; Guse, Andreas H.; Flora, Antonio De; Zocchi, Elena; Heeren, Joerg; Bruzzone, Santina

doi:10.1016/j.bbalip.2020.158819

Cited by 21 publications

(30 citation statements)

References 53 publications

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“…CD38 is an NADase that catalyzes the degradation of NAD + [ 91 , 92 , 93 ] ( Figure 3 C). This enzyme has been shown to be upregulated in a variety of diseases as well as aging [ 92 , 94 ], leading to decreased content of NAD + that would impair the function of sirtuins and poly ADP ribosylase [ 95 , 96 ]. CD38-driven NAD + deficiency has been shown to be responsible for organ fibrosis and diabetic kidney dysfunction [ 97 ].…”

Section: Pathways Of Nad + Consumption In Diabetesmentioning

confidence: 99%

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

2021

Biomolecules

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Diabetic kidney disease (DKD) is a common and severe complication of diabetes mellitus. If left untreated, DKD can advance to end stage renal disease that requires either dialysis or kidney replacement. While numerous mechanisms underlie the pathogenesis of DKD, oxidative stress driven by NADH/NAD+ redox imbalance and mitochondrial dysfunction have been thought to be the major pathophysiological mechanism of DKD. In this review, the pathways that increase NADH generation and those that decrease NAD+ levels are overviewed. This is followed by discussion of the consequences of NADH/NAD+ redox imbalance including disruption of mitochondrial homeostasis and function. Approaches that can be applied to counteract DKD are then discussed, which include mitochondria-targeted antioxidants and mimetics of superoxide dismutase, caloric restriction, plant/herbal extracts or their isolated compounds. Finally, the review ends by pointing out that future studies are needed to dissect the role of each pathway involved in NADH-NAD+ metabolism so that novel strategies to restore NADH/NAD+ redox balance in the diabetic kidney could be designed to combat DKD.

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Section: Pathways Of Nad + Consumption In Diabetesmentioning

confidence: 99%

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

2021

Biomolecules

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“…NAD + synthesis starting from NAM, 5-phosphoribosyl 1-pyrophosphate (PRPP), and ATP was evaluated as in [ 29 ]. Briefly, the different lysates were added to 100 μL reaction mixtures (3 mM ATP, 5 mM MgCl 2 , 0.5 mM PRPP, 2.5 mM NAM, 50 mM Tris-HCl, pH 7.4) and incubated at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

“…Finally, regarding CD38 and thermogenesis, a recent study demonstrated that CD38 expression is downregulated in both brown and white adipose tissues upon cold exposure, with a consequent increase in NAD + and NADP(H) levels, respectively [ 29 , 30 ]. Given the important role of CD38 in physio-pathological conditions in the liver, we investigated its role in this organ during cold-induced thermogenesis.…”

Section: Introductionmentioning

confidence: 99%

Role of Liver CD38 in the Regulation of Metabolic Pathways during Cold-Induced Thermogenesis in Mice

Benzi

Spinelli

Sturla

et al. 2022

Cells

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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 Cd38−/− 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 Cd38−/− 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 Cd38−/− 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 Cd38−/− 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 Cd38−/− mice and was not further increased by the cold. Notably, FGF21 and bile acid release was enhanced in the liver of Cd38−/− mice, which might contribute to enhanced BAT activation in Cd38−/− 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.

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“…The major NAD + -dependent redox enzymes that may be involved in cisplatin-induced kidney injury are shown in Figure 4 . These include mitochondrial complex I [ 65 , 66 ], sirtuins [ 40 , 67 , 68 ], alpha-keto acid dehydrogenases involving dihydrolipoamide dehydrogenase [ 69 ], NAD kinase (NADK) [ 70 , 71 , 72 , 73 ], CD38 [ 74 , 75 , 76 ], poly-ADP ribosylase [ 77 , 78 , 79 ], and nicotinamide nucleotide transhydrogenase (NNT) [ 57 , 80 , 81 ]. Numerous natural products that possess antioxidant activities have been shown to display antioxidant properties such as the inhibition of lipid peroxidation, DNA damage, and protein oxidation, which are collectively the popular parameters used to assess oxidative stress and antioxidant natural products [ 69 , 82 , 83 , 84 ].…”

Section: Effects Of Cisplatin On Major Individual Nad + ...mentioning

confidence: 99%

Cisplatin-Induced Kidney Toxicity: Potential Roles of Major NAD+-Dependent Enzymes and Plant-Derived Natural Products

Iskander

2022

Biomolecules

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Cisplatin is an FDA approved anti-cancer drug that is widely used for the treatment of a variety of solid tumors. However, the severe adverse effects of cisplatin, particularly kidney toxicity, restrict its clinical and medication applications. The major mechanisms of cisplatin-induced renal toxicity involve oxidative stress, inflammation, and renal fibrosis, which are covered in this short review. In particular, we review the underlying mechanisms of cisplatin kidney injury in the context of NAD+-dependent redox enzymes including mitochondrial complex I, NAD kinase, CD38, sirtuins, poly-ADP ribosylase polymerase, and nicotinamide nucleotide transhydrogenase (NNT) and their potential contributing roles in the amelioration of cisplatin-induced kidney injury conferred by natural products derived from plants. We also cover general procedures used to create animal models of cisplatin-induced kidney injury involving mice and rats. We highlight the fact that more studies will be needed to dissect the role of each NAD+-dependent redox enzyme and its involvement in modulating cisplatin-induced kidney injury, in conjunction with intensive research in NAD+ redox biology and the protective effects of natural products against cisplatin-induced kidney injury.

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CD38 downregulation modulates NAD+ and NADP(H) levels in thermogenic adipose tissues

Cited by 21 publications

References 53 publications

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

Role of Liver CD38 in the Regulation of Metabolic Pathways during Cold-Induced Thermogenesis in Mice

Cisplatin-Induced Kidney Toxicity: Potential Roles of Major NAD+-Dependent Enzymes and Plant-Derived Natural Products

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