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Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1
Abstract
In the fasted state, induction of hepatic glucose output and fatty acid oxidation is essential to sustain energetic balance. Production and oxidation of glucose and fatty acids by the liver are controlled through a complex network of transcriptional regulators. Among them, the transcriptional coactivator PGC-1α plays an important role in hepatic and systemic glucose and lipid metabolism. We have previously demonstrated that sirtuin 1 (SIRT1) regulates genes involved in gluconeogenesis through interaction and deacetylation of PGC-1α. Here, we show in vivo that hepatic SIRT1 is a factor in systemic and hepatic glucose, lipid, and cholesterol homeostasis. Knockdown of SIRT1 in liver caused mild hypoglycemia, increased systemic glucose and insulin sensitivity, and decreased glucose production. SIRT1 knockdown also decreased serum cholesterol and increased hepatic free fatty acid and cholesterol content. These metabolic phenotypes caused by SIRT1 knockdown tightly correlated with decreased expression of gluconeogenic, fatty acid oxidation and cholesterol degradation as well as efflux genes. Additionally, overexpression of SIRT1 reversed many of the changes caused by SIRT1 knockdown and depended on the presence of PGC-1α. Interestingly, most of the effects of SIRT1 were only apparent in the fasted state. Our results indicate that hepatic SIRT1 is an important factor in the regulation of glucose and lipid metabolism in response to nutrient deprivation. As these pathways are dysregulated in metabolic diseases, SIRT1 may be a potential therapeutic target to control hyperglycemia and hypercholesterolemia.
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SIRT1 protein levels are elevated in the livers of fasted mice and decrease with refeeding.
“SIRT1 protein levels are elevated in the livers of fasted mice and decrease with refeeding (Rodgers and Puigserver 2007), a regulatory pattern converse to that of SREBPs.”
From Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP (2010) · cites this paper as Rodgers and Puigserver 2007
The Discussion (p. 5) reports that SIRT1 protein is induced by fasting in mouse liver, supporting the first part of the claim. Our copy does not state that liver SIRT1 protein decreases with refeeding; fed-versus-fasted results elsewhere concern SIRT1’s effects, not that protein-level change. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSIRT1 mediates fasting-dependent regulation of multiple SREBP-1 target genes in mice.
“suggesting that SIRT1 mediates fasting-dependent regulation of multiple SREBP-1 target genes in mice (Fig. 3A-C; Rodgers and Puigserver 2007).”
From Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP (2010) · cites this paper as Rodgers and Puigserver 2007
Knockdown or knockout of SIRT1 in the mouse liver or transgenic overexpression of SIRT1 in mice results in altered lipid/cholesterol levels in serum and the liver.
“knockdown or knockout of SIRT1 in the mouse liver or transgenic overexpression of SIRT1 in mice results in altered lipid/cholesterol levels in serum and the liver (Li et al. 2007;Rodgers and Puigserver 2007;Pfluger et al. 2008;Erion et al. 2009;Purushotham et al. 2009).”
From Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP (2010) · cites this paper as Rodgers and Puigserver 2007
SIRT1 levels increase in the liver in response to fasting.
“SIRT1 levels increase in the liver in response to fasting (Rodgers and Puigserver 2007), and become more active as cellular NAD + levels rise; thus, SIRT1 is poised to modify and activate regulators of lipid mobilization.”
From Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP (2010) · cites this paper as Rodgers and Puigserver 2007
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Metadata
- Authors
- Rodgers, J. T., & Puigserver, P.
- Affiliations
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and Department of Cell Biology, Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA 02115
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-07-31
- Volume
- 104
- Issue
- 31
- Pages
- 12861-12866
- ISSN
- 0027-8424
- 1091-6490
- Cited by
- 466
- References
- 10
- Language
- en
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