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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 aggravates HFD-induced weight gain and insulin resistance. (A) Body weights, (B) liver/body weight ratio, (C) food intake, (D) fasting blood glucose levels, (E) GTT, (F) ITT, (G) area under curve (AUC) for GTT and (H) AUC for ITT of WT and KO mice fed ND or HFD. 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 1: SIRT1 deletion aggravates HFD-induced weight gain and insulin resistance. (A) Body weights, (B) liver/body weight ratio, (C) food intake, (D) fasting blood glucose levels, (E) GTT, (F) ITT, (G) area under curve (AUC) for GTT and (H) AUC for ITT of WT and KO mice fed ND or HFD. 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: We first examined the effect of SIRT1 deletion on HFD-induced changes in metabolic parameters. Body weights were significantly increased in HFD-fed WT (WH) and HFD-fed KO (KH) mice compared with ND-fed WT (WN) and ND-fed KO (KN) mice, respectively (at weeks 4, 8, and 12); additionally, KH mice had significantly elevated weight gain compared with WH mice (at weeks 4 and 8) (Fig. 1A). HFD also significantly increased liver/body weight ratio in both KO and WT mice, the fold-changes in ratio induced by HFD were greater in KO mice than in WT mice (Fig. 1B). Although food intake was lower in HFD-fed mice than in ND-fed mice, SIRT1 deletion did not significantly affect food intake in either diet (Fig. 1C).


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 aggravates HFD-induced weight gain and insulin resistance. (A) Body weights, (B) liver/body weight ratio, (C) food intake, (D) fasting blood glucose levels, (E) GTT, (F) ITT, (G) area under curve (AUC) for GTT and (H) AUC for ITT of WT and KO mice fed ND or HFD. 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 1: SIRT1 deletion aggravates HFD-induced weight gain and insulin resistance. (A) Body weights, (B) liver/body weight ratio, (C) food intake, (D) fasting blood glucose levels, (E) GTT, (F) ITT, (G) area under curve (AUC) for GTT and (H) AUC for ITT of WT and KO mice fed ND or HFD. 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: We first examined the effect of SIRT1 deletion on HFD-induced changes in metabolic parameters. Body weights were significantly increased in HFD-fed WT (WH) and HFD-fed KO (KH) mice compared with ND-fed WT (WN) and ND-fed KO (KN) mice, respectively (at weeks 4, 8, and 12); additionally, KH mice had significantly elevated weight gain compared with WH mice (at weeks 4 and 8) (Fig. 1A). HFD also significantly increased liver/body weight ratio in both KO and WT mice, the fold-changes in ratio induced by HFD were greater in KO mice than in WT mice (Fig. 1B). Although food intake was lower in HFD-fed mice than in ND-fed mice, SIRT1 deletion did not significantly affect food intake in either diet (Fig. 1C).

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