Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content
The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.
The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search: Search Advanced Clipboard User Guide Save Email Send to
Clipboard
My Bibliography
Collections
Citation manager
Display options Display options Format Abstract PubMed PMID
Email address has not been verified. Go to My NCBI account settings to confirm your email and then refresh this page. To: Subject: Body: Format: Summary Summary (text) Abstract Abstract (text) MeSH and other data Send email Cancel
Add to Collections
Create a new collection
Add to an existing collection
Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel
Add to My Bibliography
My Bibliography
Unable to load your delegates due to an error Please try again Add Cancel
Your saved search
Name of saved search: Search terms: Test search terms Would you like email updates of new search results? Saved Search Alert Radio Buttons
Yes
No
Email: (change) Frequency: Monthly Weekly Daily Which day? The first Sunday The first Monday The first Tuesday The first Wednesday The first Thursday The first Friday The first Saturday The first day The first weekday Which day? Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send at most: 1 item 5 items 10 items 20 items 50 items 100 items 200 items Send even when there aren't any new results Optional text in email: Save Cancel
Create a file for external citation management software
Create file Cancel
Your RSS Feed
Name of RSS Feed: Number of items displayed: 5 10 15 20 50 100 Create RSS Cancel RSS Link Copy
Full text links
Nature Publishing Group Free PMC article Full text links
Actions
CiteCollectionsAdd to Collections
Create a new collection
Add to an existing collection
Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an errorPlease try again Add Cancel PermalinkPermalinkCopyDisplay options Display options Format AbstractPubMedPMID
Page navigation
Title & authors
Abstract
Figures
Comment in
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Title & authors Abstract Figures Comment in References Publication types MeSH terms Substances Grants and funding LinkOut - more resources Full text links CiteDisplay options Display options Format AbstractPubMedPMID
Abstract
Nicotinamide N-methyltransferase (Nnmt) methylates nicotinamide, a form of vitamin B3, to produce N(1)-methylnicotinamide (MNAM). Nnmt has emerged as a metabolic regulator in adipocytes, but its role in the liver, the tissue with the strongest Nnmt expression, is not known. In spite of its overall high expression, here we find that hepatic expression of Nnmt is highly variable and correlates with multiple metabolic parameters in mice and humans. Further, we find that suppression of hepatic Nnmt expression in vivo alters glucose and cholesterol metabolism and that the metabolic effects of Nnmt in the liver are mediated by its product MNAM. Supplementation of high-fat diet with MNAM decreases serum and liver cholesterol and liver triglycerides levels in mice. Mechanistically, increasing Nnmt expression or MNAM levels stabilizes sirtuin 1 protein, an effect that is required for their metabolic benefits. In summary, we describe here a novel regulatory pathway for vitamin B3 that could provide a new opportunity for metabolic disease therapy.
PubMed Disclaimer
Figures
Figure 1. Nnmt regulates gluconeogenesis and cholesterol…
Figure 1. Nnmt regulates gluconeogenesis and cholesterol metabolism
( a ) Nnmt protein expression in…
Figure 1. Nnmt regulates gluconeogenesis and cholesterol metabolism (a) Nnmt protein expression in control (shcontrol) and Nnmt knockdown (shNnmt) hepatocytes. (b) Hepatocyte glucose output and mRNA expression of G6pc, Pck1 and Sirt1 in control (shcontrol) and Nnmt knockdown (shNnmt) hepatocytes (representative of 3 independent experiments performed in triplicates). (c) Nnmt protein expression in control (AdGFP) and Nnmt overexpressing (AdNnmt) hepatocytes. (d) Hepatocyte glucose output and mRNA expression of G6pc, Pck1 and Sirt1 in control (AdGFP) and Nnmt overexpressing (AdNnmt) hepatocytes (representative of >3 independent experiments performed in triplicates). (e) Overnight fasting blood glucose and insulin in mice with Nnmt knockdown (shcontrol n = 8, shNnmt n = 8). (f) Pyruvate tolerance test in mice with Nnmt knockdown (shcontrol n = 7, shNnmt n = 5). AUC = area under the curve. (g) Expression of gluconeogenic genes in the liver of Nnmt knockdown mice (shcontrol n = 8, shNnmt n = 8). (h) Serum and liver cholesterol in ad libitum fed Nnmt knockdown mice (shcontrol n = 8, shNnmt n = 7). (i) Expression of genes in cholesterol metabolism in Nnmt knockdown mice (shcontrol n = 8, shNnmt n = 7). Data are presented as mean ± s.e.m. Statistical significance was tested by unpaired Student’s t-test, *P < 0.05).
Figure 2. Human liver NNMT expression correlates…
Figure 2. Human liver NNMT expression correlates with serum cholesterol and liver inflammation
( a …
Figure 2. Human liver NNMT expression correlates with serum cholesterol and liver inflammation (a) Negative correlation between human liver NNMT expression and total cholesterol (n = 41, r = – 0.59, P < 0.0001). Subjects on hypolipidemic drugs (n = 10) were excluded from the correlation. (b) Negative correlation between human liver NNMT expression and LDL cholesterol (n = 41, r = –0.64, P < 0.0001). Subjects on hypolipidemic drugs (n = 10) were excluded from the correlation. (c) Liver NNMT expression according to liver lobular activity (index of inflammation) (n = 53, *P = 0.0367). RU = relative units.
Figure 3. Sirt1 is necessary and sufficient…
Figure 3. Sirt1 is necessary and sufficient for the metabolic effects of Nnmt
( a …
Figure 3. Sirt1 is necessary and sufficient for the metabolic effects of Nnmt (a) Immunobloting of acetylated, total FoxO1 and their ratio in control and Nnmt knockdown primary hepatocytes (triplicate determination). (b) Immunobloting of acetylated, total FoxO1 and their ratio in control and Nnmt overexpressing primary hepatocytes (triplicate determination). (c) Immunoblotting of acetylated and total FoxO1 and their ratio in the livers of control and Nnmt knockdown mice (shcontrol n = 6, shNnmt n = 7). (d) Expression of G6pc and Pck1 in control and Nnmt overexpressing primary hepatocytes treated with the Sirt1 inhibitor sirtinol (representative of 2 independent experiments performed in triplicates). (e) Expression of G6pc and Pck1 in control and Nnmt overexpressing primary hepatocytes treated with the Sirt1 inhibitor Ex-527 (performed in triplicates). (f) Effect of EX-527 on glucose production in control and Nnmt overexpressing primary hepatocytes (triplicate determination). (g) Expression of G6pc and Pck1 in control and Nnmt knockdown primary hepatocytes with Sirt1 overexpression (AdSirt1) (triplicate determination). Data are presented as mean ± s.e.m. Statistical significance was tested by unpaired Student’s t-test, *P < 0.05).
Figure 4. Nnmt regulates Sirt1 protein stability…
Figure 4. Nnmt regulates Sirt1 protein stability through its product MNAM
( a ) Sirt1…
Figure 4. Nnmt regulates Sirt1 protein stability through its product MNAM (a) Sirt1 protein and mRNA expression in control and Nnmt overexpressing primary hepatocytes (representative of 3 independent experiments performed in triplicates). (b) Sirt1 protein and mRNA expression in control and Nnmt knockdown primary hepatocytes (representative of 3 independent experiments performed in triplicates). (c) Sirt1 protein and mRNA expression in livers of control and Nnmt knockdown mice (shcontrol n = 8, shNnmt n = 8). (d) Time course of Sirt1 protein degradation in cyclohexamide-treated control and Nnmt overexpressing hepatocytes (triplicate determination). (e) Correlation between Nnmt mRNA and Sirt1 protein expression from human liver biopsies (n = 12, P = 0.797). (f) Supplementation of media with 0.1 mM MNAM increases intracellular MNAM concentration (triplicate determination). (g) Dose-dependent effect of MNAM (0–1 mM) on Sirt1 protein expression in primary hepatocytes (representative of 2 independent experiments). (h) Dose-dependent effect of MNAM (0–0.3 mM) on G6pc ,Pck1, Sirt1 and Nnmt expression in primary hepatocytes (representative of 3 independent experiments performed in triplicates). (i) Glucose production in primary hepatocytes supplemented with MNAM and infected with either control or Sirt1 knockdown adenovirus (triplicate determination). (j) G6pc and Pck1 expression in primary hepatocytes supplemented with MNAM and infected with either control or Sirt1 knockdown adenovirus (triplicate determination). Data are presented as mean ± s.e.m. Statistical significance was tested by unpaired Student’s t-test. *P < 0.05. RU = relative units.
Figure 5. MNAM improves cholesterol and lipid…
Figure 5. MNAM improves cholesterol and lipid homeostasis in DIO mice
( a ) Liver…
Figure 5. MNAM improves cholesterol and lipid homeostasis in DIO mice (a) Liver Sirt1, Actin and Sirt1 mRNA from CD, HFD, HFD0.3% and HFD1% fed mice (b) Liver acetylated and total FoxO1 from HFD and HFD1% fed mice. (c) Blood glucose (4 h fast), insulin, and quantitative insulin sensitivity index (QUICKI) of mice fed CD, HFD, HFD0.3% and HFD1%. (d) Liver TGs content of mice fed CD, HFD, HFD0.3%, HFD1% (n = 5/group) and fatty acid synthesis in primary hepatocytes from mice fed HFD and HFD1% (n = 6/group, representative of 2 independent experiments). (e) Serum cholesterol (4 h fast) on days 8, 15 and 32 from mice fed CD, HFD, HFD0.3% and HFD1%. (f) Cholesterol content of lipoprotein fractions from mice fed CD, HFD and HFD1%. (g) Liver and fecal cholesterol of mice fed CD, HFD, HFD0.3% and HFD1%. Cholesterol synthesis in primary hepatocytes from mice fed HFD and HFD1% (n = 6/group, representative of 3 independent experiments). (h) Effect of pharmacological Sirt1 inhibition on serum and liver cholesterol and liver TGs levels in mice fed a HFD, HFD1%, HFD1%+EX (n = 5/group). (i) Schematic representation of the proposed pathway. One-way ANOVA followed by posthoc Dunnett’s with control set to HFD: a,c,d,e,g and h. Unpaired t-test: b,d (right panel), g (right panel); n = 7 for CD, n = 8 for HFD, HFD0.3%, HFD1% in a,b,c,e,g (left panel); f pooled sample from 8 mice/group; g (middle panel) technical triplicate of pooled samples. Data are presented as mean ± s.e.m, *P < 0.05. See this image and copyright information in PMC
Comment in
NNMT: A Bad Actor in Fat Makes Good in Liver. Trammell SA, Brenner C.Trammell SA, et al.Cell Metab. 2015 Aug 4;22(2):200-1. doi: 10.1016/j.cmet.2015.07.017.Cell Metab. 2015.PMID: 26244929Free PMC article.
References
Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253–295. - PMC - PubMed
Houtkooper RH, Cantó C, Wanders RJ, Auwerx J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr. Rev. 2010;31:194–223. - PMC - PubMed
Bogan KL, Brenner C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu. Rev. Nutr. 2008;28:115–130. - PubMed
Rodgers JT, et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434:113–118. - PubMed
Nemoto S, Fergusson MM, Finkel T. Science. Vol. 306. New York, N.Y: 2004. Nutrient availability regulates SIRT1 through a forkhead-dependent pathway; pp. 2105–2108. - PubMed
Show all 53 references
Method-Only References
Kleiner DE, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321. - PubMed
Full text links [x] Nature Publishing Group Free PMC article [x] Cite Copy Download .nbib.nbib Format: AMA APA MLA NLM Send To
Clipboard
Email
Save
My Bibliography
Collections
Citation Manager
[x]
NCBI Literature Resources
MeSH PMC Bookshelf Disclaimer
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
Search: Search Advanced Clipboard Save Email Send to
Nature Publishing Group Free PMC article Full text links 
