Hepatocyte-specific Sirt6 deficiency impairs ketogenesis

Chen, Lei; Liu, Qinhui; Tang, Qin; Kuang, Jiangying; Li, Hong; Pu, Shiyun; Wu, Tong; Yang, Xuping; Li, Rui; Zhang, Jinhang; Zhang, Zijing; Huang, Yi; Li, Yanping; Zou, Min; Jiang, Wei; Li, Tao; Gong, Meng; Zhang, Lu; Wang, Hua; Qu, Aijuan; Xie, Wen; He, Jinhan

doi:10.1074/jbc.ra118.005309

Cited by 20 publications

(14 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mice were injected with CCl 4 to cause liver fibrosis and treated with RGD-Lip/zileuton (10 mg/kg) for 4 h. Primary hepatocytes were isolated as described ( Chen et al, 2019 ). The remaining cells were divided into three groups, fixed, perforated and stained with anti-α-SMA (HSC), anti-F4/80 (Kupffer cells) and anti-CD31 antibodies.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of 5-Lipoxygenase in Hepatic Stellate Cells Alleviates Liver Fibrosis

Liu

et al. 2021

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Background and Purpose: Activation of hepatic stellate cells (HSC) is a central driver of liver fibrosis. 5-lipoxygenase (5-LO) is the key enzyme that catalyzes arachidonic acid into leukotrienes. In this study, we examined the role of 5-LO in HSC activation and liver fibrosis.Main Methods: Culture medium was collected from quiescent and activated HSC for target metabolomics analysis. Exogenous leukotrienes were added to culture medium to explore their effect in activating HSC. Genetic ablation of 5-LO in mice was used to study its role in liver fibrosis induced by CCl4 and a methionine-choline-deficient (MCD) diet. Pharmacological inhibition of 5-LO in HSC was used to explore the effect of this enzyme in HSC activation and liver fibrosis.Key Results: The secretion of LTB4 and LTC4 was increased in activated vs. quiescent HSC. LTB4 and LTC4 contributed to HSC activation by activating the extracellular signal-regulated protein kinase pathway. The expression of 5-LO was increased in activated HSC and fibrotic livers of mice. Ablation of 5-LO in primary HSC inhibited both mRNA and protein expression of fibrotic genes. In vivo, ablation of 5-LO markedly ameliorated the CCl4- and MCD diet-induced liver fibrosis and liver injury. Pharmacological inhibition of 5-LO in HSC by targeted delivery of the 5-LO inhibitor zileuton suppressed HSC activation and improved CCl4- and MCD diet-induced hepatic fibrosis and liver injury. Finally, we found increased 5-LO expression in patients with non-alcoholic steatohepatitis and liver fibrosis.Conclusion: 5-LO may play a critical role in activating HSC; genetic ablation or pharmacological inhibition of 5-LO improved CCl4-and MCD diet-induced liver fibrosis.

show abstract

Section: Methodsmentioning

confidence: 99%

“…Western blot analysis was performed as described ( Chen et al, 2019 ). The antibodies were listed in supplementary Supplementary Table S1 .…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of 5-Lipoxygenase in Hepatic Stellate Cells Alleviates Liver Fibrosis

Liu

et al. 2021

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Serum insulin level was measured by a Rat/Mouse Insulin ELISA kit (EZRMI‐13K, Merck Millipore, Darmstadt, Germany). Levels of hepatic TG, TC, and NEFAs were determined as described 20,22 . All biochemical parameters were measured following the manufacturers’ protocols.…”

Section: Methodsmentioning

confidence: 99%

“…Our recent studies revealed that fat‐specific Sirt6 ablation sensitizes mice to diet‐induced obesity by inhibiting lipolysis 19 . In the liver, Sirt6 also inhibits the transcriptional expression of Fsp27β by interacting with Crebh, promoting the production of ketone body 20 . In addition to peripheral tissues, Sirt6 has a critical central role in regulating energy homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Sirtuin 6 supra‐physiological overexpression in hypothalamic pro‐opiomelanocortin neurons promotes obesity via the hypothalamus‐adipose axis

et al. 2021

Self Cite

View full text Add to dashboard Cite

Sirtuin 6 (Sirt6), a member of the Sirtuin family, has important roles in maintaining glucose and lipid metabolism. Our previous studies demonstrated that the deletion of Sirt6 in pro‐opiomelanocortin (POMC)‐expressing cells by the loxP‐Cre system resulted in severe obesity and hepatic steatosis. However, whether overexpression of Sirt6 in hypothalamic POMC neurons could ameliorate diet‐induced obesity is still unknown. Thus, we generated mice specifically overexpressing Sirt6 in hypothalamic POMC neurons (PSOE) by stereotaxic injection of Cre‐dependent adeno‐associated viruses into the arcuate nucleus of Pomc‐Cre mice. PSOE mice showed increased adiposity and decreased energy expenditure. Furthermore, thermogenesis of BAT and lipolysis of WAT were both impaired, caused by reduced sympathetic nerve innervation and activity in adipose tissues. Mechanistically, Sirt6 overexpression decreasing STAT3 acetylation, thus lowering POMC expression in the hypothalamus underlined the observed phenotypes in PSOE mice. These results demonstrate that Sirt6 overexpression specifically in the hypothalamic POMC neurons exacerbates diet‐induced obesity and metabolic disorders via the hypothalamus‐adipose axis.

show abstract

Sirt6 deletion in hepatocytes increases insulin sensitivity of female mice by enhancing ERα expression

Tang

Liu

Zhou

et al. 2019

Journal Cellular Physiology

View full text Add to dashboard Cite

Sirtuin 6 (Sirt6), a NAD+‐dependent protein deacetylase, is involved in hepatic glucose metabolism and insulin sensitivity, which impact metabolic homeostasis. In this paper, we discover that Sirt6 affects the insulin sensitivity of mice in a gender‐dependent manner; few studies have been conducted on this issue. Based on reports revealing the influences of sex hormones on insulin signaling, this investigation explores the mechanism by which Sirt6 regulates the estrogen pathway and disrupts insulin signal transduction. Hepatocyte‐specific Sirt6 knockout (Sirt6HKO) mice were generated to investigate the function of Sirt6 in hepatocytes. Mice were castrated or spayed to eliminate sex hormones. Insulin sensitivity was assessed via an insulin tolerance test (ITT) in vivo. The interaction of Sirt6 with the estrogen pathway and their impacts on insulin signal transduction were revealed by immunoblot and immunoprecipitation. Sirt6 deletion in hepatocytes significantly enhanced insulin sensitivity and signal transduction in female mice but not in male or spayed female mice as demonstrated by ITT and the phosphorylation level of Akt in the liver. We also identified upregulation of p300, ERα, and interaction of ERα with p85 in the liver of female Sirt6HKO mice. Additionally, Sirt6 was found to inhibit ERα protein stability in a p300‐dependent manner without interacting directly with ERα. Our findings show that hepatic Sirt6 downregulates the ERα protein level in a p300‐dependent manner and thus disturbs estrogen‐induced improvement in insulin sensitivity in the liver, which may partially explain the gender difference in insulin sensitivity.

show abstract

Hepatocyte-specific Sirt6 deficiency impairs ketogenesis

Cited by 20 publications

References 51 publications

Inhibition of 5-Lipoxygenase in Hepatic Stellate Cells Alleviates Liver Fibrosis

Inhibition of 5-Lipoxygenase in Hepatic Stellate Cells Alleviates Liver Fibrosis

Sirtuin 6 supra‐physiological overexpression in hypothalamic pro‐opiomelanocortin neurons promotes obesity via the hypothalamus‐adipose axis

Sirt6 deletion in hepatocytes increases insulin sensitivity of female mice by enhancing ERα expression

Contact Info

Product

Resources

About