Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice.
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.
Yamazaki
Yu
Y
First Dept. of Internal Medicine, Univ. of Toyama, 2630 Sugitani Toyama 930-0194, Japan.
Usui
Isao
I
Kanatani
Yukiko
Y
Matsuya
Yuji
Y
Tsuneyama
Koichi
K
Fujisaka
Shiho
S
Bukhari
Agussalim
A
Suzuki
Hikari
H
Senda
Satoko
S
Imanishi
Shingo
S
Hirata
Kazuya
K
Ishiki
Manabu
M
Hayashi
Ryuji
R
Urakaze
Masaharu
M
Nemoto
Hideo
H
Kobayashi
Masashi
M
Tobe
Kazuyuki
K
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D004435:Eating / Q000187:drug effects; D005234:Fatty Liver / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D050356:Lipid Metabolism / Q000187:drug effects*; D050155:Lipogenesis / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D060888:Real-Time Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000378:metabolism*; D012970:Sodium Glutamate
D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D012970:Sodium Glutamate