Dall 2021 J Biol Chem

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Dall M, Hassing AS, Niu L, Nielsen TS, Ingerslev LR, Sulek K, Trammell SAJ, Gillum MP, Barrès R, Larsen S, Poulsen SS, Mann M, Ørskov C, Treebak JT (2021) Hepatocyte-specific perturbation of NAD+ biosynthetic pathways in mice induces reversible nonalcoholic steatohepatitis-like phenotypes. J Biol Chem [Epub ahead of print].

» PMID: 34762911 Open Access

Dall Morten, Hassing Anna S, Niu Lili, Nielsen Thomas S, Ingerslev Lars R, Sulek Karolina, Trammell Samuel A J, Gillum Matthew P, Barres Romain, Larsen Steen, Poulsen Steen S, Mann Matthias, Oerskov Cathrine, Treebak Jonas T (2021) J Biol Chem

Abstract: Nicotinamide phosphoribosyltransferase (NAMPT) converts nicotinamide to nicotinamide adenine dinucleotide (NAD+). As low hepatic NAD+ levels have been linked to the development of nonalcoholic fatty liver disease (NAFLD), we hypothetized 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, choline-free 60% high-fat diet (MCD), hepatocyte-specific Nampt knockout mice (HNKO) accumulated less triglyceride than wild-type 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 (PD). This HNKO phenotype was also associated with decreased abundance of mitochondrial proteins, especially proteins involved in oxidoreductase activity. High-resolution respirometry revealed lower respiratory capacity in PD-fed HNKO liver. In addition, fibrotic area in HNKO liver sections negatively correlated with hepatic NAD+, and liver injury was prevented by supplementation with NAD+ precursors nicotinamide riboside (NR) and nicotinic acid. Mass spectrometry (MS)-based proteomic analysis revealed that NR supplementation rescued hepatic levels of oxidoreductase- and OXPHOS proteins. Finally, single nucleus RNAseq 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 due to 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 NAFLD progression. Keywords: NAD(+) biosynthesis; NAMPT, Fibrosis, Hepatocyte, Mitochondria, Nicotinamide adenine dinucleotide (NAD) Bioblast editor: Plangger M O2k-Network Lab: DK Copenhagen Larsen S


Labels: MiParea: Respiration, Genetic knockout;overexpression, Exercise physiology;nutrition;life style  Pathology: Other 

Organism: Mouse  Tissue;cell: Liver  Preparation: Intact cells 


Coupling state: LEAK, OXPHOS, ET  Pathway: N, NS  HRR: Oxygraph-2k, O2k-Fluorometer 

2021-11, AmR