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Myeloid-specific SIRT1 Deletion Aggravates Hepatic Inflammation and Steatosis in High-fat Diet-fed Mice.

Kim KE, Kim H, Heo RW, Shin HJ, Yi CO, Lee DH, Kim HJ, Kang SS, Cho GJ, Choi WS, Roh GS - Korean J. Physiol. Pharmacol. (2015)

Bottom Line: In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-κB), hepatic inflammation and macrophage infiltration.Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis.Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Korea.

ABSTRACT
Sirtuin 1 (SIRT1) is a mammalian NAD(+)-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-κB), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.

No MeSH data available.


Related in: MedlinePlus

SIRT1 deletion increases NF-κB acetylation and induces NF-κB nuclear translocation in HFD-fed mice. Western blots of SIRT1 (A) and acetylated NF-κB p65 (B) in liver homogenates from WT and KO mice fed ND or HFD. (C, D) Western blots of cytosolic and nuclear NF-κB and the nuclear/cytosolic (N/C) ratio of NF-κB levels. Band intensity was normalized to β-actin or α-tubulin. Data are presented as mean±SEM. *p<0.05 for WH mice versus WN mice. †p<0.05 for KH mice versus KN mice. #p<0.05 for KH mice versus WH mice. WN, ND-fed WT mice; WH, HFD-fed WT mice; KN, ND-fed KO mice; KH, HFD-fed KO mice.
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Figure 2: SIRT1 deletion increases NF-κB acetylation and induces NF-κB nuclear translocation in HFD-fed mice. Western blots of SIRT1 (A) and acetylated NF-κB p65 (B) in liver homogenates from WT and KO mice fed ND or HFD. (C, D) Western blots of cytosolic and nuclear NF-κB and the nuclear/cytosolic (N/C) ratio of NF-κB levels. Band intensity was normalized to β-actin or α-tubulin. Data are presented as mean±SEM. *p<0.05 for WH mice versus WN mice. †p<0.05 for KH mice versus KN mice. #p<0.05 for KH mice versus WH mice. WN, ND-fed WT mice; WH, HFD-fed WT mice; KN, ND-fed KO mice; KH, HFD-fed KO mice.

Mentions: SIRT1 is known to suppress inflammatory responses by deacetylating NF-κB p65 [17] and thus, we investigated the correlation between hepatic SIRT1 and acetylated NF-κB expression. SIRT1 expression was decreased in KO mice compared with WT mice due to SIRT1 silencing in myeloid-derived liver macrophages (Kupffer cells), and the level was further reduced by HFD (Fig. 2A). As previously reported [17], we confirmed the reduced SIRT1 expression in liver and epididymal fat of KO mice in which myeloid-derived cells, Kupffer cells and peritoneal macrophages are enriched, respectively (Supplementary Fig. 1B). Among sirtuin family, SIRT1 and SIRT3 are closely related proteins as belonging to class I sirtuins [18]. However, the expression of mitochondrial SIRT3 in liver of both WT and KO was not affected by myeloid SIRT1 deletion (Supplementary Fig. 2).


Myeloid-specific SIRT1 Deletion Aggravates Hepatic Inflammation and Steatosis in High-fat Diet-fed Mice.

Kim KE, Kim H, Heo RW, Shin HJ, Yi CO, Lee DH, Kim HJ, Kang SS, Cho GJ, Choi WS, Roh GS - Korean J. Physiol. Pharmacol. (2015)

SIRT1 deletion increases NF-κB acetylation and induces NF-κB nuclear translocation in HFD-fed mice. Western blots of SIRT1 (A) and acetylated NF-κB p65 (B) in liver homogenates from WT and KO mice fed ND or HFD. (C, D) Western blots of cytosolic and nuclear NF-κB and the nuclear/cytosolic (N/C) ratio of NF-κB levels. Band intensity was normalized to β-actin or α-tubulin. Data are presented as mean±SEM. *p<0.05 for WH mice versus WN mice. †p<0.05 for KH mice versus KN mice. #p<0.05 for KH mice versus WH mice. WN, ND-fed WT mice; WH, HFD-fed WT mice; KN, ND-fed KO mice; KH, HFD-fed KO mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4553405&req=5

Figure 2: SIRT1 deletion increases NF-κB acetylation and induces NF-κB nuclear translocation in HFD-fed mice. Western blots of SIRT1 (A) and acetylated NF-κB p65 (B) in liver homogenates from WT and KO mice fed ND or HFD. (C, D) Western blots of cytosolic and nuclear NF-κB and the nuclear/cytosolic (N/C) ratio of NF-κB levels. Band intensity was normalized to β-actin or α-tubulin. Data are presented as mean±SEM. *p<0.05 for WH mice versus WN mice. †p<0.05 for KH mice versus KN mice. #p<0.05 for KH mice versus WH mice. WN, ND-fed WT mice; WH, HFD-fed WT mice; KN, ND-fed KO mice; KH, HFD-fed KO mice.
Mentions: SIRT1 is known to suppress inflammatory responses by deacetylating NF-κB p65 [17] and thus, we investigated the correlation between hepatic SIRT1 and acetylated NF-κB expression. SIRT1 expression was decreased in KO mice compared with WT mice due to SIRT1 silencing in myeloid-derived liver macrophages (Kupffer cells), and the level was further reduced by HFD (Fig. 2A). As previously reported [17], we confirmed the reduced SIRT1 expression in liver and epididymal fat of KO mice in which myeloid-derived cells, Kupffer cells and peritoneal macrophages are enriched, respectively (Supplementary Fig. 1B). Among sirtuin family, SIRT1 and SIRT3 are closely related proteins as belonging to class I sirtuins [18]. However, the expression of mitochondrial SIRT3 in liver of both WT and KO was not affected by myeloid SIRT1 deletion (Supplementary Fig. 2).

Bottom Line: In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-κB), hepatic inflammation and macrophage infiltration.Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis.Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Korea.

ABSTRACT
Sirtuin 1 (SIRT1) is a mammalian NAD(+)-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-κB), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.

No MeSH data available.


Related in: MedlinePlus