METHIONINE RESTRICTION ALTERS HEPATIC MIRNAS INVOLVED IN METABOLISM IN YOUNG, OBESE, AND AGED MICE

Age-associated disorders, such as Type II diabetes and nonalcoholic fatty liver disease, can be regulated by microRNAs. Dietary methionine restriction (MR) in young mice reduces adiposity and increases glucose sensitivity. The aim of this study was to determine whether previously identified miRNAs altered by MR in livers of young mice were similarly regulated in diet-induced obese (DIO) mice and aged mice. Young and aged male (8-week-old and 18-month-old, respectively) C57BL/6J mice were fed either a control (0.86% methionine; CF) or MR (0.12% methionine) diet; DIO mice (12-weeks-old; 40 grams) were fed a high–fat (60%) CF or MR diet for 12 weeks. MR repressed hepatic expression of several miRNAs (miR-455-5p, miR-33-5p, miR-99a-5p, and let-7g-5p) and increased the expression of mRNAs (Scarb1, Abcb11, Irs2, Insr, mTor, and Hadhb) that regulate the synthesis and transport of cholesterol, bile acids, fatty acids, and insulin in both young and DIO mice. However, in aged mice, miR-33-5p and miR-99a-5p, which regulate bile acid transport and mTOR signaling, respectively, were not affected by MR, while let-7g-5p, which regulates insulin signaling, was increased. MiR-455-5p, which can target Scarb1 and regulate cholesterol synthesis, remained repressed by MR. These findings suggest that the benefits of MR on liver function in young and DIO mice appear to be achieved through multiple mechanisms to attenuate a fatty liver condition, and that only some of these mechanisms are still effective in old mice.