Tissue-specific regulation of sirtuin and nicotinamide adenine dinucleotide biosynthetic pathways identified in C57Bl/6 mice in response to high-fat feeding

Drew, Janice E.; Farquharson, Andrew J.; Horgan, Graham; Williams, Lynda M.

doi:10.1016/j.jnutbio.2016.07.013

Cited by 32 publications

(24 citation statements)

References 38 publications

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“…This suggests that impaired NAD ϩ salvage may be an important factor for disease development. However, we and others have observed increased NAD ϩ and NAMPT levels in livers of high-fat diet (HFD)-fed mice (40) or little or no change in hepatic NAD ϩ content following long-term HFD feeding (41)(42)(43). This suggests that hepatic lipid accumulation per se may not cause a shortage of NAD ϩ or impair NAD ϩ salvage capacity.…”

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confidence: 68%

Mitochondrial function in liver cells is resistant to perturbations in NAD+ salvage capacity

Dall

Trammell

Asping

et al. 2019

Journal of Biological Chemistry

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Edited by John M. Denu 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.

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confidence: 68%

Mitochondrial function in liver cells is resistant to perturbations in NAD+ salvage capacity

Dall

Trammell

Asping

et al. 2019

Journal of Biological Chemistry

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“…Interestingly, similar to the rhythmic binding of BMAL1 and NPAS2 around CT8 and the PER and CRY proteins at CT16 on the Nampt promoter, the promoter of Nmrk1 was bound by BMAL1, CLOCK around CT6, and PER2 around CT16. Although BMAL1, CRY1, and CRY2 also bound the promoter of Nmnat3 around CT0 and PER2 bound at CT16, they have apparently minor effect on its expression (Figure 4E), which is likely regulated by additional transcription factors regulated by food-derived signals, potentially contributing to its dysregulation observed in obesity (Drew et al, 2016; Jukarainen et al, 2016). Taken together, these results highlighted the fact that not only the NAD + salvage pathway but also the feeding-related NR pathway are influenced by the circadian clock and that both play an important role in clock-regulated NAD + synthesis.…”

Section: Resultsmentioning

confidence: 99%

Circadian and Feeding Rhythms Orchestrate the Diurnal Liver Acetylome

et al. 2017

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SummaryLysine acetylation is involved in various biological processes and is considered a key reversible post-translational modification in the regulation of gene expression, enzyme activity, and subcellular localization. This post-translational modification is therefore highly relevant in the context of circadian biology, but its characterization on the proteome-wide scale and its circadian clock dependence are still poorly described. Here, we provide a comprehensive and rhythmic acetylome map of the mouse liver. Rhythmic acetylated proteins showed subcellular localization-specific phases that correlated with the related metabolites in the regulated pathways. Mitochondrial proteins were over-represented among the rhythmically acetylated proteins and were highly correlated with SIRT3-dependent deacetylation. SIRT3 activity being nicotinamide adenine dinucleotide (NAD)+ level-dependent, we show that NAD+ is orchestrated by both feeding rhythms and the circadian clock through the NAD+ salvage pathway but also via the nicotinamide riboside pathway. Hence, the diurnal acetylome relies on a functional circadian clock and affects important diurnal metabolic pathways in the mouse liver.

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“…Serial dilutions of a standard sample were included for each gene to generate a standard curve. Values were normalized to ubiquitin-conjugating enzyme E2D 2A (Ube2d2a) expression levels [26]. The primer sequences are shown in S1 Table.…”

Section: Methodsmentioning

confidence: 99%

JDP2 and ATF3 deficiencies dampen maladaptive cardiac remodeling and preserve cardiac function

et al. 2019

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c-Jun dimerization protein (JDP2) and Activating Transcription Factor 3 (ATF3) are closely related basic leucine zipper proteins. Transgenic mice with cardiac expression of either JDP2 or ATF3 showed maladaptive remodeling and cardiac dysfunction. Surprisingly, JDP2 knockout (KO) did not protect the heart following transverse aortic constriction (TAC). Instead, the JDP2 KO mice performed worse than their wild type (WT) counterparts. To test whether the maladaptive cardiac remodeling observed in the JDP2 KO mice is due to ATF3, ATF3 was removed in the context of JDP2 deficiency, referred as double KO mice (dKO). Mice were challenged by TAC, and followed by detailed physiological, pathological and molecular analyses. dKO mice displayed no apparent differences from WT mice under unstressed condition, except a moderate better performance in dKO male mice. Importantly, following TAC the dKO hearts showed low fibrosis levels, reduced inflammatory and hypertrophic gene expression and a significantly preserved cardiac function as compared with their WT counterparts in both genders. Consistent with these data, removing ATF3 resumed p38 activation in the JDP2 KO mice which correlates with the beneficial cardiac function. Collectively, mice with JDP2 and ATF3 double deficiency had reduced maladaptive cardiac remodeling and lower hypertrophy following TAC. As such, the worsening of the cardiac outcome found in the JDP2 KO mice is due to the elevated ATF3 expression. Simultaneous suppression of both ATF3 and JDP2 activity is highly beneficial for cardiac function in health and disease.

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Tissue-specific regulation of sirtuin and nicotinamide adenine dinucleotide biosynthetic pathways identified in C57Bl/6 mice in response to high-fat feeding

Cited by 32 publications

References 38 publications

Mitochondrial function in liver cells is resistant to perturbations in NAD+ salvage capacity

Mitochondrial function in liver cells is resistant to perturbations in NAD+ salvage capacity

Circadian and Feeding Rhythms Orchestrate the Diurnal Liver Acetylome

JDP2 and ATF3 deficiencies dampen maladaptive cardiac remodeling and preserve cardiac function

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