SLC16a6, mTORC1, and Autophagy Regulate Ketone Body Excretion in the Intestinal Cells

Author:

Uebanso Takashi1,Fukui Moeka1,Naito Chisato1,Shimohata Takaaki12,Mawatari Kazuaki1ORCID,Takahashi Akira1

Affiliation:

1. Department of Preventive Environment and Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan

2. Faculty of Marine Biosciences, Fukui Prefectural University, Fukui 917-0003, Japan

Abstract

Ketone bodies serve several functions in the intestinal epithelium, such as stem cell maintenance, cell proliferation and differentiation, and cancer growth. Nevertheless, there is limited understanding of the mechanisms governing the regulation of intestinal ketone body concentration. In this study, we elucidated the factors responsible for ketone body production and excretion using shRNA-mediated or pharmacological inhibition of specific genes or functions in the intestinal cells. We revealed that a fasting-mimicked culture medium, which excluded glucose, pyruvate, and glutamine, augmented ketone body production and excretion in the Caco2 and HT29 colorectal cells. This effect was attenuated by glucose or glutamine supplementation. On the other hand, the inhibition of the mammalian target of rapamycin complex1 (mTORC1) recovered a fraction of the excreted ketone bodies. In addition, the pharmacological or shbeclin1-mediated inhibition of autophagy suppressed ketone body excretion. The knockdown of basigin, a transmembrane protein responsible for targeting monocarboxylate transporters (MCTs), such as MCT1 and MCT4, suppressed lactic acid and pyruvic acid excretion but increased ketone body excretion. Finally, we found that MCT7 (SLC16a6) knockdown suppressed ketone body excretion. Our findings indicate that the mTORC1–autophagy axis and MCT7 are potential targets to regulate ketone body excretion from the intestinal epithelium.

Funder

JSPS KAKENHI

Publisher

MDPI AG

Subject

General Agricultural and Biological Sciences,General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology

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