Hepatic mitochondrial NAD+ transporter SLC25A47 activates AMPKα mediating lipid metabolism and tumorigenesis

Hepatic mitochondrial NAD+ transporter SLC25A47 activates AMPKα mediating lipid metabolism and tumorigenesis

Hepatology

10.1097/HEP.0000000000000314

http://dx.doi.org/10.1097/hep.0000000000000314

Lili Cheng, R.N.V. Krishna Deepak, Guoqiang Wang, Ziyi Meng, Lei Tao, Mengqing Xie, Wenna Chi, Yuming Zhang, Mingming Yang, Yilie Liao, Ruiqun Chen, Yu Liang, Junyu Zhang, Yuedong Huang, Weihua Wang, Zhiying Guo, Yunfang Wang, Jiandie D. Lin, Hao Fan, Ligong Chen

20 February 2023

Cheng, L., Deepak, R. N. V. K., Wang, G., Meng, Z., Tao, L., Xie, M., Chi, W., Zhang, Y., Yang, M., Liao, Y., Chen, R., Liang, Y., Zhang, J., Huang, Y., Wang, W., Guo, Z., Wang, Y., Lin, J. D., Fan, H., & Chen, L. (2023). Hepatic mitochondrial NAD+ transporter SLC25A47 activates AMPKα mediating lipid metabolism and tumorigenesis. Hepatology, 78(6), 1828–1842. https://doi.org/10.1097/hep.0000000000000314

Background & Aims: SLC25A47 was initially identified as a mitochondrial HCC-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to investigate the physiological role of SLC25A47 in hepatic metabolism. Approach & Results: In the treatment of hepatocytes with metformin, we found that metformin can transcriptionally activate the expression of Slc25a47, which is required for AMP-activated protein kinase α (AMPKα) phosphorylation. Slc25a47-deficient mice had increased hepatic lipid content, triglycerides, and cholesterol levels, and we found that Slc25a47 deficiency suppressed AMPKα phosphorylation and led to an increased accumulation of nuclear SREBPs, with elevated fatty acid and cholesterol biosynthetic activities. Conversely, when Slc25a47 was overexpressed in mouse liver, AMPKα was activated and resulted in the inhibition of lipogenesis. Moreover, using a diethylnitrosamine-induced mouse HCC model, we found that the deletion of Slc25a47 promoted HCC tumorigenesis and development through the activated mammalian target of rapamycin cascade. Employing homology modeling of SLC25A47 and virtual screening of the human metabolome database, we demonstrated that NAD+ was an endogenous substrate for SLC25A47, and the activity of NAD+-dependent sirtuin 3 declined in Slc25a47-deficient mice, followed by inactivation of AMPKα. Conclusions: Our findings reveal that SLC25A47, a hepatocyte-specific mitochondrial NAD+ transporter, is one of the pharmacological targets of metformin and regulates lipid homeostasis through AMPKα, and may serve as a potential drug target for treating NAFLD and HCC.

Attribution 4.0 International (CC BY 4.0)

This research is supported by core funding from: Biomedical Research Council of Agency for Science, Technology, and Research (A*STAR) - Bioinformatics
Grant Reference no. : NA

This work is supported by the National Natural Science Foundation of China (32130048, 91857108, 92157301, and 31971085, the Ministry of Science and Technology of China National Key R&D Programs (2022YFA0806503, 2018YFA0506903, Tsinghua-Foshan Innovation Special Fund (TFISF, 2020THFS0133, Tsinghua Precision medicine foundation (2022TS013, Tsinghua University Spring Breeze Fund (2021Z99CFY012).

https://oar.a-star.edu.sg/communities-collections/articles/20654

0270-9139

Bioinformatics Institute