Nonalcoholic fatty liver disease (NAFLD) is an abnormal liver metabolism often observed with insulin resistance and metabolic syndrome. Calorie restriction is a useful treatment for NAFLD and reportedly prolongs the life spans of several species in which sirtuin plays an important role. In this study, we examined whether the activation of SIRT1, a mammalian ortholog of sirtuin, may ameliorate the development of NAFLD. Monosodium glutamate (MSG) mice, which exhibited obesity and insulin resistance, were treated with SRT1720, a specific SIRT1 activator from the age of 6-16 wk. Sixteen-week-old MSG mice exhibited increased liver triglyceride content and elevated levels of aminotransferase. SRT1720 treatment significantly reduced these levels without affecting body weight or food intake. These results suggested that the administration of SRT1720 ameliorated the development of NAFLD in MSG mice. The expressions of lipogenic genes, such as sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase, and the serum lipid profiles, including free fatty acids, were elevated in MSG mice and were reduced by SRT1720 treatment. SRT1720 treatment also reduced the expressions of lipogenic genes in cultured HepG2 cells. Furthermore, SRT1720 treatment decreased the expressions of marker genes for oxidative stress and inflammatory cytokines in the liver of MSG mice. Taken together, SRT1720 treatment may reduce liver lipid accumulation, at least in part, by directly reducing the expressions of lipogenic genes. The reduction of oxidative stress and inflammation may also be involved in the amelioration of NAFLD.

The Sirt1 activator SRT1720 suppressed inflammatory cell infiltration and cytokine production in an OVA-induced mouse model of asthma. SRT1720 and resveratrol suppressed OVA-induced splenocyte proliferation and TNF-α and IL-6 production. Sirt1 activators might have beneficial effects in asthmatics by suppressing inflammation.

Abstract. Silent information regulator 2 (SIR2) is a highly conserved protein, the mammalian orthologue of which, SIRT1, exhibits histone deacetylase activity. SIRT1 is involved not in only longevity due to caloric restriction but in a variety of diseases such as diabetes, cardiovascular dysfunction and neurodegeneration. However, accumulating evidence shows that SIRT1 is overexpressed in various types of malignant cells, and its inhibitors suppress the growth of tumor cells. The relationship between SIRT1 and metastasis remains to be clarified. Here, we examined the effect of SRT1720, a SIRT1 activator, on lung metastasis of breast cancer cells. 4T1 breast cancer cells were subcutaneously implanted into syngeneic BALB/c mice and SRT1720 was administered alone or with an antitumor agent, cisplatin. As expected, cisplatin decreased the lung metastasis score, whereas SRT1720 increased metastasis irrespective of cisplatin. In the primary tumors, cisplatin suppressed the mRNA level of angiopoietin-like protein 4 (ANGPTL4), a lung metastasis-promoting gene product of breast cancer, but SRT1720 reduced the effectiveness of cisplatin. The results obtained with animal experiments were in accordance with those in human cancer cells; SRT1720 significantly increased the amount of VEGF secreted from MDA-MB-231 cells. Moreover, a transendothelial cell migration assay showed that SRT1720 promotes the migration of MDA-MB-231 cells across an endothelial cell layer despite the presence of cisplatin. These findings imply that SRT1720 promotes the pulmonary metastasis of breast cancer cells and SIRT1 may be an important target for suppressing metastasis to the lung. IntroductionMetastasis is a poorly understood process in cancer biology despite extensive study (1). It comprises multiple steps; movement of cells from the primary tumor into the surrounding tissues, penetration of blood and lymphatic vessels, extravasation into the organ parenchyma, and proliferation to form metastatic colonies at secondary sites. These steps require the coordinated actions of numerous genes (2,3). Several studies have recently clarified that cancer cells regulate the expression of specific genes involved in the targeted colonization of other organs; these genes include an 18-gene breast-to-lung metastatic gene-expression signature, such as angiopoietinlike protein 4 (ANGPTL4), epidermal growth factor receptor ligand epiregulin, prostaglandin-endoperoxide synthase 2 (also known as COX2), matrix metalloproteinase-1, and other mediators associated with infiltration of cancer cells and subsequent colonization in the lung (4,5).Silent information regulator 2 (SIR2) is a highly conserved protein found from yeast to humans. The mammalian Sirtuin family is comprised of seven members (6) and SIRT1 is the mammalian SIR2 orthologue which exhibits histone deacetylase activity (HDAC). It is well established that caloric restriction expands lifespan in a variety of species, in which SIRT1 plays the role of a principal modulator (7-9). On the other hand, SIRT1 exp...

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It is suggested that TTP and tumor response in second-line chemotherapy, serum levels of LDH and hemoglobin, and BMI at initiation of third-line chemotherapy could be possible prognostic factors.