ChREBP is known to play a critical role in the development of obesity and diabetes by regulating hepatic lipogenesis. High-sucrose diet (HSD) feeding is known to cause irritable bowel syndrome-like phenotype in ChREBP knockout mice (KO) with some alterations in gut microbiota. However, effects of the gut microbiota alteration on whole-body metabolism in KO remains unknown. Twelve-week old wild type mice (WT) and KO, both fed on HSD for 7 days, were analyzed. KO had 3-fold higher cecum contents compared to WT (WT, 71±24.4; and KO, 205.7±46.0 g). KO had a remarkable increase in acetate-producing bacteria (e.g., Bifidobacterium and Bacteroides) in the cecum. Consistently, KO showed 2-fold higher acetate levels in the cecum (WT, 27.5±6.0; and KO, 55.6±22.3 μmoles/g stool). Interestingly, KO also showed higher hepatic acetate contents (WT, 0.81±0.18; and 1.08±0.14 μmoles/g liver). Since acetate is converted into acetyl-CoA; and used for lipogenesis, ketogenesis and protein acetylation, we investigated hepatic triglyceride contents, plasma 3OHBA levels and histone acetylation. While hepatic acetyl-CoA contents and plasma 3-OHBA levels did not differ between the two groups, hepatic triglyceride contents were much lower in KO (WT, 11.45±5.47; and KO, 4,11±0.44 mg/g liver), consistent with reduced expression of hepatic lipogenic genes. In contrast, histone acetylation on selected genes (e.g., Fasn, Chrebp and Pklr) was significantly enhanced in KO. These results together indicated that increased supply of acetyl-CoA in the liver, possibly due to enhanced acetate-production in the gut and reduced hepatic lipogenesis, leads to enhancement of histone acetylation in KO, while physiological relevance awaits further investigation.


K. Iizuka: Speaker’s Bureau; Self; Kowa Company, Ltd., Novo Nordisk Inc. K. Takao: None. Y. Liu: None. K. Nonomura: None. T. Kato: None. M. Mizuno: None. Y. Horikawa: None. D. Yabe: Research Support; Self; ARKRAY, Astellas Pharma Inc., AstraZeneca K.K., Eli Lilly Japan K.K., Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Kowa Company, Ltd., Nippon Boehringer Ingelheim Co. Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Abbott, ARKRAY, Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo, Eli Lilly Japan K.K., Fukuda Denshi, Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., LifeScan, Inc., Medtronic, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Novo Nordisk Inc., Sanofi K.K., Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Other Relationship; Self; Japan Diabetes Society.


Grant-in-Aid for Scientific Research (17K00850)

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