SIRT1 and insulin resistance

Cao, Yilin; Jiang, Xinli; Ma, Huijie; Wang, Yuling; Xue, Peng; Liu, Yan

doi:10.1016/j.jdiacomp.2015.08.022

Cited by 114 publications

(80 citation statements)

References 93 publications

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“…We speculated before that increased acetylation of FoxO3 might be due to a decrease in SIRT1 protein levels (5). Loss of SIRT1 has also been shown to be associated with insulin resistance (37, 38). Here we found that miR-34a targeted SIRT1 protein.…”

Section: Discussionmentioning

confidence: 99%

FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis

Natarajan¹,

Stringham

Mohr

et al. 2017

Journal of Lipid Research

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Nonalcoholic steatohepatitis (NASH) patients have elevated plasma saturated free fatty acid levels. These toxic fatty acids can induce liver cell death and our recent results demonstrated that the biliary epithelium may be susceptible to lipotoxicity. Here, we explored the molecular mechanisms of cholangiocyte lipoapoptosis in cell culture and in an animal model of NASH. Treatment of cholangiocytes with palmitate (PA) showed increased caspase 3/7 activity and increased levels of cleaved poly (ADP-ribose) polymerase and cleaved caspase 3, demonstrating cholangiocyte lipoapoptosis. Interestingly, treatment with PA significantly increased the levels of microRNA miR-34a, a pro-apoptotic microRNA known to be elevated in NASH. PA induction of miR-34a was abolished in cholangiocytes transduced with forkhead family of transcription factor class O (FoxO)3 shRNA, demonstrating that FoxO3 activation is upstream of miR-34a and suggesting that FoxO3 is a novel transcriptional regulator of miR-34a. Further, anti-miR-34a protected cholangiocytes from PA-induced lipoapoptosis. Direct and indirect targets of miR-34a, such as SIRT1, receptor tyrosine kinase (MET), Kruppel-like factor 4, fibroblast growth factor receptor (FGFR)1, and FGFR4, were all decreased in PA-treated cholangiocytes. SIRT1 and MET were partially rescued by a miR-34a antagonist. Cholangiocyte apoptosis and miR-34a were dramatically increased in the liver of mice with early histologic features of NASH. Our study provides evidence for the pro-apoptotic role of miR-34a in PA-induced cholangiocyte lipoapoptosis in culture and in the liver.

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Section: Discussionmentioning

confidence: 99%

FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis

Natarajan¹,

Stringham

Mohr

et al. 2017

Journal of Lipid Research

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“…5B), thus confirming a critical role of MAPK activation in high-glucose induction of RTA expression. To investigate other mechanisms that might be involved in high-glucose induction of KSHV lytic replication, we examined the expression of SIRT1, which is a member of the class III HDACs and a key factor involved in the development of diabetes (34)(35)(36)(37)(38)(39)(40). In addition, several previous studies demonstrated the involvement of SIRT1 in the regulation of KSHV lytic gene expression through epigenetic remodeling (41)(42)(43).…”

Section: Methodsmentioning

confidence: 99%

High Glucose Induces Reactivation of Latent Kaposi's Sarcoma-Associated Herpesvirus

Zeng

Sha

et al. 2016

J Virol

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A high prevalence of Kaposi's sarcoma (KS) is seen in diabetic patients. It is unknown if the physiological conditions of diabetes contribute to KS development. We found elevated levels of viral lytic gene expression when Kaposi's sarcoma-associated herpesvirus (KSHV)-infected cells were cultured in high-glucose medium. To demonstrate the association between high glucose levels and KSHV replication, we xenografted telomerase-immortalized human umbilical vein endothelial cells that are infected with KSHV (TIVE-KSHV cells) into hyperglycemic and normal nude mice. The injected cells expressed significantly higher levels of KSHV lytic genes in hyperglycemic mice than in normal mice. We further demonstrated that high glucose levels induced the production of hydrogen peroxide (H 2 O 2 ), which downregulated silent information regulator 1 (SIRT1), a class III histone deacetylase (HDAC), resulting in the epigenetic transactivation of KSHV lytic genes. These results suggest that high blood glucose levels in diabetic patients contribute to the development of KS by promoting KSHV lytic replication and infection. IMPORTANCEMultiple epidemiological studies have reported a higher prevalence of classic KS in diabetic patients. By using both in vitro and in vivo models, we demonstrated an association between high glucose levels and KSHV lytic replication. High glucose levels induce oxidative stress and the production of H 2 O 2 , which mediates the reactivation of latent KSHV through multiple mechanisms. Our results provide the first experimental evidence and mechanistic support for the association of classic KS with diabetes. K aposi's sarcoma (KS) is a vascular neoplasia etiologically associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection (1). KSHV establishes a lifelong persistent latent infection following acute infection. Reactivation of the latent virus into productive lytic replication plays a pivotal role in the initiation and progression of KS, as viral load positively correlates with KS progression. Indeed, treatment of KS patients with antiherpesvirus drugs effectively leads to regression of KS tumors (2-6).Unlike iatrogenic or AIDS-associated KS, classic KS occurs predominantly in elderly men of Mediterranean or Jewish descent who have no apparent immune suppression (7). The exact cause of the development of classic KS remains undefined. Asthma, allergies in males, topical corticosteroid use, and infrequent bathing have been suggested to be risk factors for classic KS (8,9). Multiple studies have also documented a high prevalence of classic KS in patients with diabetes mellitus (10-13), a metabolic syndrome that manifests with elevated levels of blood glucose and episodic ketoacidosis, due to either a lack of insulin (type 1 diabetes) or cellular resistance to insulin (type 2 diabetes). High levels of KSHV DNA and seropositivity have been seen in diabetic patients (14-16). However, no study has ever determined if diabetes is the cause or an effect of KS and whether high glucose levels play ...

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“…Indeed, it was demonstrated that SIRT-1, a NAD + -dependent histone deacetylase, regulates the glucose and lipid metabolism by deacetylating several key metabolic effectors (61). Silencing the expression of SIRT-1 was demonstrated to result in insulin resistance, type 2 diabetes mellitus (T2DM), and dyslipidemias, which are all recognized adverse effects of atypical APDs (17, 62). In addition, blocking the expression of VEGF was associated with hypercholesterolemia and insulin resistance (63–65).…”

Section: Cvae and Metabolic Adverse Effects Of Apds: Same Pathogenesimentioning

confidence: 99%

The Ticking of the Epigenetic Clock: Antipsychotic Drugs in Old Age

et al. 2016

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BackgroundExposed to antipsychotic drugs (APDs), older individuals with dementing illness are at risk of cerebrovascular adverse effects (CVAE), including sudden death. Transient microvascular dysfunctions are known to occur in younger persons exposed to APDs; however, they seldom progress to CVAE, suggesting that APDs alone are insufficient for engendering this untoward effect. It is, therefore, believed that a preexistent microvascular damage is necessary for CVAE to take place, but the exact nature of this lesion remains unclear. CNS small vessel disease (SVD) is a well-known age-related risk factor for strokes, dementia, and sudden death, which may constitute the initial CVAE-predisposing pathology. Therefore, we propose the two strikes CVAE paradigm, in which SVD represents the first strike, while exposure to APDs, the second. In this model, both strikes must be present for CVAE to take place, and the neuroimaging load of white matter hyperintensities may be directly proportional with the CVAE risk. To investigate this hypothesis at the molecular level, we focused on a seemingly unrelated phenomenon: both APDs and SVD were found protective against a similar repertoire of cancers and their spread to the brain (1–4). Since microRNA-29 has shown efficacy against the same malignancies and has been associated with small vessels pathology, we narrowed our search down to this miR, hypothesizing that the APDs mechanism of action includes miR-29 upregulation, which in turn facilitates the development of SVD.AimTo assess whether miR-29 can be utilized as a peripheral blood biomarker for SVD and CVAE risk.MethodWe conducted a search of experimentally verified miR-29 target genes utilizing the public domain tools miRanda, RNA22 and Weizemann Institute of Science miRNA Analysis. We identified in total 67 experimentally verified target genes for miR-29 family, 18 of which correlate with microvascular integrity and may be relevant for CVAE.ConclusionUpregulated microRNA-29 silences the expression of 18 genes connected with capillary stability, engendering a major vulnerability for SVD (first strike) which in turn increases the risk for CVAE after exposure to APDs (second strike).

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SIRT1 and insulin resistance

Cited by 114 publications

References 93 publications

FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis

FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis

High Glucose Induces Reactivation of Latent Kaposi's Sarcoma-Associated Herpesvirus

The Ticking of the Epigenetic Clock: Antipsychotic Drugs in Old Age

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