Effects of black vinegar, Kurozu, on chromatin modifications and microRNA expression in the mouse liver

Background: Kurozu is a traditional Japanese rice vinegar characterized by its brown color and that has been shown to improve hypertension, hypercholesterolemia, and carbohydrate metabolism. Kurozu has also been suggested to confer health benefits by altering gene expression; however, the molecular basis is not yet understood. Objective: We previously reported that the intake of Kurozu increased the expression hepatic Sirt1 and microRNA (miR). These changes in gene expression may be attributed to histone modifications. Therefore, the current research explored the effects of supplementation with concentrated Kurozu (CK) on histone modifications in the liver. Methods: Over a period of 50 weeks, mice received a high-fat diet (HFD), HFD with CK, or a standard diet (SD). The study focused on the impact of CK on gene expression related to lipid metabolism in the liver. Results: A microarray analysis revealed that HFD increased the expression of the miR cluster located on chromosome 12, while this change was suppressed by CK. The chromatin modification region upstream of the miR cluster was analyzed using a Chip assay. HFD significantly increased the levels of dimethylation of histone H3 lysine 4 (H3K4me2) and monoacetylation of histone H3 lysine 27 (H3K27ac). HFD also increased H3K4me2 levels, and this change was inhibited by HFD with CK. MiR-127-5p and -134-5p, which are present in the miR cluster, inhibited MLXIPL, a transcription factor involved in synthesizing fatty acids from carbohydrates. Further experiments with human colon cancer cells demonstrated that miR-127-5p and -134-5p significantly knocked down MLXIPL. Conclusion: These results suggested that HFD affects miR expression levels by changing chromatin modification levels and that supplementation with CK suppressed HFD-induced increases in H3K4me2 levels. Furthermore, HFD upregulated the expression of miR-127-5p and -134-5p, which in turn suppressed MLXIPL. Keywords: chromatin modification, genomic imprinting, high-fat diet, Kurozu, microRNA, MLXIPL