Abstract
The quantity and quality of dietary protein profoundly influence satiety, body growth, and systemic metabolism. Among the 20 major proteinogenic amino acids, arginine (Arg) is considerably associated with hepatic steatosis; when animals fed an Arg-deficient diet (ΔArg), triacylglyceride (TAG) dramatically accumulates in the liver. To explore the underlying mechanism, we first investigated the role of ornithine (Orn), as Orn is the primary metabolite of Arg and it is reportedly involved in the regulation of liver metabolism. While male Wistar rats fed a ΔArg diet exhibited a significant increase in liver TAG levels due to an attenuated TAG secretion, and consistently marked reduction of TAG-rich lipoproteins in the circulation, Orn addition to the diet completely abolished all these metabolic changes. Orn was only effective when taken orally, but not through intraperitoneal administration, suggesting that the intestine plays an essential role for Orn to regulate liver metabolism. The metabolic features similar to those of our rat model was also observed in the analyses of clinical samples, implying the common mechanism in humans. Conclusively, dietary Arg deficiency lowers local Arg-to-Orn conversion in the intestine, which in turn inhibits hepatic lipid secretion remotely via gut-liver axis.
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Data availability
Raw 16 S ribosomal DNA amplicon sequencing data related to Supplementary Fig 5 are available in the DDBJ BioProject database with links to BioProject accession number #PRJDB40630. The human datasets generated and/or analyzed in this study are not publicly available for protecting personal privacy, but are available upon reasonable request. The other data described in this manuscript and the analytical code will be made available upon reasonable request. Further information and requests should be directed to and will be fulfilled by the lead contact, Hiroki Nishi ([shwest@mail.saitama-u.ac.jp](mailto: shwest@mail.saitama-u.ac.jp)).
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Acknowledgements
We thank Dr. Minoru Yoshida and Dr. Yasuhiro Ogata (Japanese Red Cross Kumamoto Health Care Center) for the human data collection. We also thank Ms. Tomomi Ueda and Ms. Noyumi Nakamura (Department of Veterinary Medical Sciences, the University of Tokyo) for their technical support. Further, we thank Dr. Shin-Ichiro Takahashi (The University of Tokyo) for his contribution in supervising our experiments. We would like to thank Editage (www.editage.com) for the English language editing.
Funding
This work was supported in part by the Japan Society for the Promotion of Science (JSPS) KAKENHI, #23K13923 granted to H.N., 24K21295 and 23K27558 granted to M.R.Z.; 15H04583, 23H00358 and 23K23793 granted to F.H.; and the Moonshot Research and Development Program (##21zf0127003h001) granted to M.R.Z.; and the Cross-ministerial Moonshot Agriculture, Forestry, and Fishers Research, from the Bio-oriented Technology Research Advancement Institution, BRAIN (#20350956) granted to N.H. and F.H.
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H.N. designed the study; H.N. and S.N. conducted most experiments; L.X., M.F., Y.Z., and M.R.Z. contributed to 11 C-Orn synthesis and related experiments; D.Y. contributed to LC-MS-based metabolite analyses; J.S. and K.O. collected human blood samples, performed human data curation, examined patients, and collected clinical samples; S.F. contributed to the clinical data processing and informatics analyses; F.H. supervised the study; H.N., S.F., and F.H. wrote the manuscript. All the authors have read and approved the final version of the manuscript.
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Nishi, H., Nakanishi, S., Xie, L. et al. Remote regulation of hepatic lipid secretion in the intestine by metabolic interaction of dietary arginine with ornithine. Sci Rep (2026). https://doi.org/10.1038/s41598-026-47841-8
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DOI: https://doi.org/10.1038/s41598-026-47841-8
