Abstract
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.
Originalsprog | Engelsk |
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Artikelnummer | 101388 |
Tidsskrift | Journal of Biological Chemistry |
Vol/bind | 297 |
Udgave nummer | 6 |
Antal sider | 26 |
ISSN | 0021-9258 |
DOI | |
Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:Funding and additional information—This work was funded by grants obtained by J. T. T. from the Novo Nordisk Foundation (Excellence Project Award, NNF14OC0009315) and the Danish Council for Independent Research (DFF 4004-00235 and 0134-00217B). Support was also provided by the Novo Nordisk Foundation Center of Basic Metabolic Research (https://cbmr.ku.dk), which is an independent research center at the University of Copenhagen, and partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900). M. D. and A. S. H. were each awarded a PhD stipend from the Danish Diabetes Academy, supported by the Novo Nordisk Foundation. M. D. was awarded a postdoctoral stipend from the Danish Diabetes Academy (NNF17SA0031406). This work was also supported by the Novo Nordisk Foundation for the Clinical Proteomics group (NNF15CC0001).
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© 2021 THE AUTHORS.