Mitochondrial function in liver cells is resistant to perturbations in NAD+ salvage capacity
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Mitochondrial function in liver cells is resistant to perturbations in NAD+ salvage capacity. / Dall, Morten; Trammell, Samuel A. J.; Asping, Magnus; Hassing, Anna S; Agerholm, Marianne; Vienberg, Sara G; Gillum, Matthew P; Larsen, Steen; Treebak, Jonas T.
I: The Journal of Biological Chemistry, Bind 294, Nr. 36, 2019, s. 13304-13326.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Mitochondrial function in liver cells is resistant to perturbations in NAD+ salvage capacity
AU - Dall, Morten
AU - Trammell, Samuel A. J.
AU - Asping, Magnus
AU - Hassing, Anna S
AU - Agerholm, Marianne
AU - Vienberg, Sara G
AU - Gillum, Matthew P
AU - Larsen, Steen
AU - Treebak, Jonas T.
N1 - © 2019 Dall et al.
PY - 2019
Y1 - 2019
N2 - Supplementation with NAD precursors such as nicotinamide riboside (NR) has been shown to enhance mitochondrial function in the liver and to prevent hepatic lipid accumulation in high-fat diet (HFD)-fed rodents. Hepatocyte-specific knockout of the NAD+-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT) reduces liver NAD+ levels, but the metabolic phenotype of Nampt-deficient hepatocytes in mice is unknown. Here, we assessed Nampt's role in maintaining mitochondrial and metabolic functions in the mouse liver. Using the Cre-LoxP system, we generated hepatocyte-specific Nampt knockout (HNKO) mice, having a 50% reduction of liver NAD+ levels. We screened the HNKO mice for signs of metabolic dysfunction following 60% HFD feeding for 20 weeks ± NR supplementation and found that NR increases hepatic NAD+ levels without affecting fat mass or glucose tolerance in HNKO or WT animals. High-resolution respirometry revealed that NR supplementation of the HNKO mice did not increase state III respiration, which was observed in WT mice following NR supplementation. Mitochondrial oxygen consumption and fatty-acid oxidation were unaltered in primary HNKO hepatocytes. Mitochondria isolated from whole-HNKO livers had only a 20% reduction in NAD+, suggesting that the mitochondrial NAD+ pool is less affected by HNKO than the whole-tissue pool. When stimulated with tryptophan in the presence of [15N]glutamine, HNKO hepatocytes had a higher [15N]NAD+ enrichment than WT hepatocytes, indicating that HNKO mice compensate through de novo NAD+ synthesis. We conclude that NAMPT-deficient hepatocytes can maintain substantial NAD+ levels and that the Nampt knockout has only minor consequences for mitochondrial function in the mouse liver.
AB - Supplementation with NAD precursors such as nicotinamide riboside (NR) has been shown to enhance mitochondrial function in the liver and to prevent hepatic lipid accumulation in high-fat diet (HFD)-fed rodents. Hepatocyte-specific knockout of the NAD+-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT) reduces liver NAD+ levels, but the metabolic phenotype of Nampt-deficient hepatocytes in mice is unknown. Here, we assessed Nampt's role in maintaining mitochondrial and metabolic functions in the mouse liver. Using the Cre-LoxP system, we generated hepatocyte-specific Nampt knockout (HNKO) mice, having a 50% reduction of liver NAD+ levels. We screened the HNKO mice for signs of metabolic dysfunction following 60% HFD feeding for 20 weeks ± NR supplementation and found that NR increases hepatic NAD+ levels without affecting fat mass or glucose tolerance in HNKO or WT animals. High-resolution respirometry revealed that NR supplementation of the HNKO mice did not increase state III respiration, which was observed in WT mice following NR supplementation. Mitochondrial oxygen consumption and fatty-acid oxidation were unaltered in primary HNKO hepatocytes. Mitochondria isolated from whole-HNKO livers had only a 20% reduction in NAD+, suggesting that the mitochondrial NAD+ pool is less affected by HNKO than the whole-tissue pool. When stimulated with tryptophan in the presence of [15N]glutamine, HNKO hepatocytes had a higher [15N]NAD+ enrichment than WT hepatocytes, indicating that HNKO mice compensate through de novo NAD+ synthesis. We conclude that NAMPT-deficient hepatocytes can maintain substantial NAD+ levels and that the Nampt knockout has only minor consequences for mitochondrial function in the mouse liver.
U2 - 10.1074/jbc.RA118.006756
DO - 10.1074/jbc.RA118.006756
M3 - Journal article
C2 - 31320478
VL - 294
SP - 13304
EP - 13326
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 36
ER -
ID: 227417862