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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 hepatic CTGF and α-SMA expression in HFD-fed mice. (A) Western blots of CTGF in liver homogenates from WT and KO mice fed ND or HFD. (B) Immunohistochemistry for CTGF detection in liver sections. (C) Western blots of α-SMA in liver homogenates from WT and KO mice fed ND or HFD. (D) Immunohistochemistry for α-SMA detection in liver sections. Band intensity was normalized to β-actin. 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. Scale bar=100 µm.
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Figure 5: SIRT1 deletion increases hepatic CTGF and α-SMA expression in HFD-fed mice. (A) Western blots of CTGF in liver homogenates from WT and KO mice fed ND or HFD. (B) Immunohistochemistry for CTGF detection in liver sections. (C) Western blots of α-SMA in liver homogenates from WT and KO mice fed ND or HFD. (D) Immunohistochemistry for α-SMA detection in liver sections. Band intensity was normalized to β-actin. 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. Scale bar=100 µm.

Mentions: We examined hepatic expression of connective tissue growth factor (CTGF) and alpha-smooth muscle actin (α-SMA) which are indicative of hepatic fibrogenesis (Fig. 5). CTGF and α-SMA are overexpressed in the patients with severe hepatic fibrosis [2223]. Compared with WH or KN mice, KH mice showed a significant increase in hepatic CTGF expression and CTGF-positive immuno-stained cells (Fig. 5A and B). In addition, KH mice showed a significant increase in hepatic α-SMA expression and α-SMA -positive immuno-stained cells (Fig. 5C and D).


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 hepatic CTGF and α-SMA expression in HFD-fed mice. (A) Western blots of CTGF in liver homogenates from WT and KO mice fed ND or HFD. (B) Immunohistochemistry for CTGF detection in liver sections. (C) Western blots of α-SMA in liver homogenates from WT and KO mice fed ND or HFD. (D) Immunohistochemistry for α-SMA detection in liver sections. Band intensity was normalized to β-actin. 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. Scale bar=100 µm.
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Related In: Results  -  Collection

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Figure 5: SIRT1 deletion increases hepatic CTGF and α-SMA expression in HFD-fed mice. (A) Western blots of CTGF in liver homogenates from WT and KO mice fed ND or HFD. (B) Immunohistochemistry for CTGF detection in liver sections. (C) Western blots of α-SMA in liver homogenates from WT and KO mice fed ND or HFD. (D) Immunohistochemistry for α-SMA detection in liver sections. Band intensity was normalized to β-actin. 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. Scale bar=100 µm.
Mentions: We examined hepatic expression of connective tissue growth factor (CTGF) and alpha-smooth muscle actin (α-SMA) which are indicative of hepatic fibrogenesis (Fig. 5). CTGF and α-SMA are overexpressed in the patients with severe hepatic fibrosis [2223]. Compared with WH or KN mice, KH mice showed a significant increase in hepatic CTGF expression and CTGF-positive immuno-stained cells (Fig. 5A and B). In addition, KH mice showed a significant increase in hepatic α-SMA expression and α-SMA -positive immuno-stained cells (Fig. 5C and D).

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