| First Author | Dall M | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 36 | Pages | 13304-13326 |
| PubMed ID | 31320478 | Mgi Jnum | J:281345 |
| Mgi Id | MGI:6369258 | Doi | 10.1074/jbc.RA118.006756 |
| Citation | Dall M, et al. (2019) Mitochondrial function in liver cells is resistant to perturbations in NAD(+) salvage capacity. J Biol Chem 294(36):13304-13326 |
| abstractText | 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 [(15)N]glutamine, HNKO hepatocytes had a higher [(15)N]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. |
