Reprogramming of rhythmic liver metabolism by intestinal clock

Chen, Min1; Lin, Yanke1; Dang, Yongkang1; Xiao, Yifei1; Zhang, Fugui1; Sun, Guanghui1; Jiang, Xuejun1; Zhang, Li1; Du, Jianhao1; Duan, Shuyi2; Zhang, Xiaojian2; Qin, Zifei2; Yang, Jing2; Liu, Kaisheng3,4; Wu, Baojian1

2023-09-01

10.1016/j.jhep.2023.04.040

JOURNAL OF HEPATOLOGY   Impact Factor & Quartile

0168-8278

1600-0641

Background & Aims: Temporal oscillations in intestinal nutrient processing and absorption are coordinated by the local clock, which leads to the hypothesis that the intestinal clock has major impacts on shaping peripheral rhythms via diurnal nutritional signals. Here, we investigate the role of the intestinal clock in controlling liver rhythmicity and metabolism.Methods: Transcriptomic analysis, metabolomics, metabolic assays, histology, quantitative (q)PCR, and immunoblotting were performed with Bmal1-intestine-specific knockout (iKO), Rev-erba-iKO, and control mice.Results: Bmal1 iKO caused large-scale reprogramming of the rhythmic transcriptome of mouse liver with a limited effect on its clock. In the absence of intestinal Bmal1, the liver clock was resistant to entrainment by inverted feeding and a high-fat diet. Importantly, Bmal1 iKO remodelled diurnal hepatic metabolism by shifting to gluconeogenesis from lipogenesis during the dark phase, leading to elevated glucose production (hyperglycaemia) and insulin insensitivity. Conversely, Rev-erba iKO caused a diversion to lipogenesis from gluconeogenesis during the light phase, resulting in enhanced lipogenesis and an increased sus-ceptibility to alcohol-related liver injury. These temporal diversions were attributed to disruption of hepatic SREBP-1c rhythmicity, which was maintained via gut-derived polyunsaturated fatty acids produced by intestinal FADS1/2 under the control of a local clock.Conclusions: Our findings establish a pivotal role for the intestinal clock in dictating liver rhythmicity and diurnal metabolism, and suggest targeting intestinal rhythms as a new avenue for improving metabolic health.& COPY; 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Circadian rhythm Intestine clock SREBP Metabolic diseases

SCI

English

NI Journal Papers

Corresponding

National Key R&D Program of China["2020YFC2008300","2020YFC2008304"] ; Young Elite Scientists Sponsorship Program by Henan Association for Science and Technology[2022HYTP045] ; National Natural Science Foundation of China[82273040] ; Science and Technology Foundation of Shenzhen[JCYJ20200109144410181]

Gastroenterology & Hepatology

Gastroenterology & Hepatology

WOS:001064964000001

ELSEVIER

CLINICAL MEDICINE

Web of Science

1.Guangzhou Univ Chinese Med, Inst Mol Rhythm & Metab, Guangzhou, Peoples R China
2.Zhengzhou Univ, Dept Pharm, Affiliated Hosp 1, Zhengzhou, Peoples R China
3.Jinan Univ, Guangdong Prov Clin Res Ctr Geriatr, Shenzhen Clin Res Ctr Geriatr, Shenzhen Peoples Hosp,Clin Med Coll 2, Shenzhen, Guangdong, Peoples R China
4.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen, Guangdong, Peoples R China

Chen, Min,Lin, Yanke,Dang, Yongkang,et al. Reprogramming of rhythmic liver metabolism by intestinal clock[J]. JOURNAL OF HEPATOLOGY,2023,79(3).

Chen, Min.,Lin, Yanke.,Dang, Yongkang.,Xiao, Yifei.,Zhang, Fugui.,...&Wu, Baojian.(2023).Reprogramming of rhythmic liver metabolism by intestinal clock.JOURNAL OF HEPATOLOGY,79(3).

Chen, Min,et al."Reprogramming of rhythmic liver metabolism by intestinal clock".JOURNAL OF HEPATOLOGY 79.3(2023).