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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 hepatic steatosis in HFD-fed mice. (A) Histological analysis of hepatic fat accumulation by H&E and Oil Red O staining. Scale bar=100 µm. (B) Western blots of nuclear SREBP1 in liver homogenates from WT and KO mice fed an ND or HFD. Band intensity was normalized to nuclear p84 protein. (C) Hepatic TG levels in supernatant fractions of liver homogenates. 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 4: SIRT1 deletion aggravates hepatic steatosis in HFD-fed mice. (A) Histological analysis of hepatic fat accumulation by H&E and Oil Red O staining. Scale bar=100 µm. (B) Western blots of nuclear SREBP1 in liver homogenates from WT and KO mice fed an ND or HFD. Band intensity was normalized to nuclear p84 protein. (C) Hepatic TG levels in supernatant fractions of liver homogenates. 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: Hepatic steatosis is characterized by accumulation of TG vacuoles and hepatomegaly, which is an early stage of liver damage and could further develop into hepatic fibrosis and cirrhosis [21]. To assess the phenotype of hepatic steatosis, we performed hematoxylin and eosin (H&E) and Oil Red O staining (Fig. 4A). We found that WH and KH mice exhibited enlarged cytoplasmic lipid droplets compared to WN and KN mice, and lipid droplet sizes were larger in KH mice than in WH mice (Fig. 4A). Oil Red O-positive areas (%) in WN and WH mice were 7.71±0.58 and 32.85±1.27, respectively; the positive areas (%) in KN and KH mice were 15.01±0.72 and 40.19±2.13, respectively. The results demonstrate that KN mice showed a mild hepatic steatosis phenotype that was aggravated by HFD.


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 hepatic steatosis in HFD-fed mice. (A) Histological analysis of hepatic fat accumulation by H&E and Oil Red O staining. Scale bar=100 µm. (B) Western blots of nuclear SREBP1 in liver homogenates from WT and KO mice fed an ND or HFD. Band intensity was normalized to nuclear p84 protein. (C) Hepatic TG levels in supernatant fractions of liver homogenates. 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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Figure 4: SIRT1 deletion aggravates hepatic steatosis in HFD-fed mice. (A) Histological analysis of hepatic fat accumulation by H&E and Oil Red O staining. Scale bar=100 µm. (B) Western blots of nuclear SREBP1 in liver homogenates from WT and KO mice fed an ND or HFD. Band intensity was normalized to nuclear p84 protein. (C) Hepatic TG levels in supernatant fractions of liver homogenates. 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: Hepatic steatosis is characterized by accumulation of TG vacuoles and hepatomegaly, which is an early stage of liver damage and could further develop into hepatic fibrosis and cirrhosis [21]. To assess the phenotype of hepatic steatosis, we performed hematoxylin and eosin (H&E) and Oil Red O staining (Fig. 4A). We found that WH and KH mice exhibited enlarged cytoplasmic lipid droplets compared to WN and KN mice, and lipid droplet sizes were larger in KH mice than in WH mice (Fig. 4A). Oil Red O-positive areas (%) in WN and WH mice were 7.71±0.58 and 32.85±1.27, respectively; the positive areas (%) in KN and KH mice were 15.01±0.72 and 40.19±2.13, respectively. The results demonstrate that KN mice showed a mild hepatic steatosis phenotype that was aggravated by HFD.

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