Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice

Abstract

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.

SRT1720, a SIRT1 activator, promotes tumor cell migration, and lung metastasis of breast cancer in mice

“…We examined the effect of SRT1720 on the pulmonary metastasis of inoculated 4T1 cells as well as the size and weight of primary tumors. Our previous results showed that the oral administration of SRT1720 to normal mice did not affect body weight or food intake at a dose of 200 mg/kg over a period of 70 days (18). Therefore, SRT1720 was given at a dose of 100 mg/kg body weight.…”

“…The activity of SRT1720 as a SIRT1 activator is stronger than that of resveratrol. We previously reported that SRT1720 treatment decreased the expression of marker genes responsible for oxidative stress and inflammatory cytokines in the liver of monosodium glutamate (MSG)-injected ICR mice, a murine model of severe obesity and insulin resistance (18). While SIRT1 expression is upregulated in various cancers and SIRT1 inhibitors suppress cancer cell growth in vivo and in vitro, the relationship between the function of SIRT1 and cancer metastasis remains to be characterized.…”

Sirtuins as novel players in the pathogenesis of diabetes mellitus

“…SIRT1 activators might induce insulin secretion and sensitivity, reduce adipogenesis, but also induce gluconeogenesis in the liver which may worsen hyperglycemia in diabetes mellitus. Recently, Yamazaki et al [61] showed that treatment of mice with nonalcoholic fatty liver disease with a synthetic SIRT1 activator, SRT1720, might decrease the serum lipid levels, oxidative stress and inflammation. In addition, Feige et al [62] suggested that activation of SIRT1 via SRT1720 protected the organism from diet-induced obesity and insulin resistance by increasing oxidation of fatty acids in liver, adipose tissue and skeletal muscle.…”

Dietary Interventions to Extend Life Span and Health Span Based on Calorie Restriction

“…One of the compounds, sRT1720, has been shown to mitigate various negative effects of obesity and high-fat diets in both rats and mice (96)(97)(98). sRT1720 has also been shown to induce a transcriptional profile in mice reminiscent of CR, eliciting parallel changes in genes associated with mitochondrial biogenesis, metabolic signaling, and inflammatory pathways (99).…”