Hepatocyte-specific perturbation of NAD + biosynthetic pathways in mice induces reversible nonalcoholic steatohepatitis-like phenotypes.
| Autor: | Dall M; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Hassing AS; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Niu L; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark., Nielsen TS; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Ingerslev LR; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Sulek K; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark., Trammell SAJ; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Gillum MP; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Barrès R; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Larsen S; Department of Biomedical Sciences, Xlab, Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark; Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland., Poulsen SS; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Mann M; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany., Ørskov C; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Treebak JT; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. Electronic address: jttreebak@sund.ku.dk. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of biological chemistry [J Biol Chem] 2021 Dec; Vol. 297 (6), pp. 101388. Date of Electronic Publication: 2021 Nov 08. |
| DOI: | 10.1016/j.jbc.2021.101388 |
| Abstrakt: | Nicotinamide phosphoribosyltransferase (NAMPT) converts nicotinamide to NAD + . As low hepatic NAD + levels have been linked to the development of nonalcoholic fatty liver disease, we hypothesized that ablation of hepatic Nampt would affect susceptibility to liver injury in response to diet-induced metabolic stress. Following 3 weeks on a low-methionine and choline-free 60% high-fat diet, hepatocyte-specific Nampt knockout (HNKO) mice accumulated less triglyceride than WT littermates but had increased histological scores for liver inflammation, necrosis, and fibrosis. Surprisingly, liver injury was also observed in HNKO mice on the purified control diet. This HNKO phenotype was associated with decreased abundance of mitochondrial proteins, especially proteins involved in oxidoreductase activity. High-resolution respirometry revealed lower respiratory capacity in purified control diet-fed HNKO liver. In addition, fibrotic area in HNKO liver sections correlated negatively with hepatic NAD + , and liver injury was prevented by supplementation with NAD + precursors nicotinamide riboside and nicotinic acid. MS-based proteomic analysis revealed that nicotinamide riboside supplementation rescued hepatic levels of oxidoreductase and OXPHOS proteins. Finally, single-nucleus RNA-Seq showed that transcriptional changes in the HNKO liver mainly occurred in hepatocytes, and changes in the hepatocyte transcriptome were associated with liver necrosis. In conclusion, HNKO livers have reduced respiratory capacity, decreased abundance of mitochondrial proteins, and are susceptible to fibrosis because of low NAD + levels. Our data suggest a critical threshold level of hepatic NAD + that determines the predisposition to liver injury and supports that NAD + precursor supplementation can prevent liver injury and nonalcoholic fatty liver disease progression. Competing Interests: Conflict of interests The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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