Combined metabolic activators decrease liver steatosis by activating mitochondrial metabolism in hamsters fed with a high-fat diet

Hong Yang; Jordi Mayneris-Perxachs; Noemí Boqué; Josep M. Del Bas; Lluís Arola; Meng Yuan; Hasan Türkez; Mathias Uhlén; Jan Borén; Cheng Zhang; Adil Mardinoglu; Antoni Caimari

doi:10.3390/biomedicines9101440

Combined metabolic activators decrease liver steatosis by activating mitochondrial metabolism in hamsters fed with a high-fat diet

Hong Yang, Jordi Mayneris-Perxachs, Noemí Boqué, Josep M. Del Bas, Lluís Arola, Meng Yuan, Hasan Türkez, Mathias Uhlén, Jan Borén, Cheng Zhang, Adil Mardinoglu^*, Antoni Caimari

^*Corresponding author for this work

Centre for Host Microbiome Interactions

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

Although the prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase, there is no effective treatment approved for this condition. We previously showed, in high-fat diet (HFD)-fed mice, that the supplementation of combined metabolic activators (CMA), including nicotinamide riboside (NAD⁺ precursor) and the potent glutathione precursors serine and N-acetyl-l-cysteine (NAC), significantly decreased fatty liver by promoting fat oxidation in mitochondria. Afterwards, in a one-day proof-of-concept human supplementation study, we observed that this CMA, including also L-carnitine tartrate (LCT), resulted in increased fatty acid oxidation and de novo glutathione synthesis. However, the underlying molecular mechanisms associated with sup-plementation of CMA have not been fully elucidated. Here, we demonstrated in hamsters that the chronic supplementation of this CMA (changing serine for betaine) at two doses significantly decreased hepatic steatosis. We further generated liver transcriptomics data and integrated these data using a liver-specific genome-scale metabolic model of liver tissue. We systemically determined the molecular changes after the supplementation of CMA and found that it activates mitochondria in the liver tissue by modulating global lipid, amino acid, antioxidant and folate metabolism. Our findings provide extra evidence about the beneficial effects of a treatment based on this CMA against NAFLD.

Original language	English
Article number	1440
Journal	Biomedicines
Volume	9
Issue number	10
Early online date	11 Oct 2021
DOIs	https://doi.org/10.3390/biomedicines9101440
Publication status	Published - Oct 2021

Keywords

Combined metabolic activators
Mitochondrial metabolism
NAFLD
Transcriptomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/biomedicines9101440

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Yang, H., Mayneris-Perxachs, J., Boqué, N., Del Bas, J. M., Arola, L., Yuan, M., Türkez, H., Uhlén, M., Borén, J., Zhang, C., Mardinoglu, A., & Caimari, A. (2021). Combined metabolic activators decrease liver steatosis by activating mitochondrial metabolism in hamsters fed with a high-fat diet. Biomedicines, 9(10), Article 1440. https://doi.org/10.3390/biomedicines9101440

@article{df4fd6a8f870418489d199de7c79ead3,

title = "Combined metabolic activators decrease liver steatosis by activating mitochondrial metabolism in hamsters fed with a high-fat diet",

abstract = "Although the prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase, there is no effective treatment approved for this condition. We previously showed, in high-fat diet (HFD)-fed mice, that the supplementation of combined metabolic activators (CMA), including nicotinamide riboside (NAD+ precursor) and the potent glutathione precursors serine and N-acetyl-l-cysteine (NAC), significantly decreased fatty liver by promoting fat oxidation in mitochondria. Afterwards, in a one-day proof-of-concept human supplementation study, we observed that this CMA, including also L-carnitine tartrate (LCT), resulted in increased fatty acid oxidation and de novo glutathione synthesis. However, the underlying molecular mechanisms associated with sup-plementation of CMA have not been fully elucidated. Here, we demonstrated in hamsters that the chronic supplementation of this CMA (changing serine for betaine) at two doses significantly decreased hepatic steatosis. We further generated liver transcriptomics data and integrated these data using a liver-specific genome-scale metabolic model of liver tissue. We systemically determined the molecular changes after the supplementation of CMA and found that it activates mitochondria in the liver tissue by modulating global lipid, amino acid, antioxidant and folate metabolism. Our findings provide extra evidence about the beneficial effects of a treatment based on this CMA against NAFLD.",

keywords = "Combined metabolic activators, Mitochondrial metabolism, NAFLD, Transcriptomics",

author = "Hong Yang and Jordi Mayneris-Perxachs and Noem{\'i} Boqu{\'e} and {Del Bas}, {Josep M.} and Llu{\'i}s Arola and Meng Yuan and Hasan T{\"u}rkez and Mathias Uhl{\'e}n and Jan Bor{\'e}n and Cheng Zhang and Adil Mardinoglu and Antoni Caimari",

note = "Funding Information: This research was funded by the Agency for Business Competitiveness of the Government of Catalonia (ACCI?), grant number: TECCT11?1-0012; This work was financially supported by the Centre for the Development of Industrial Technology (CDTI) of the Spanish Ministry of Science and Innovation under grant agreement: TECNOMIFOOD project: CER-20191010; This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation, grant number: 72110. Funding Information: Funding: This research was funded by the Agency for Business Competitiveness of the Government of Catalonia (ACCI{\'O}), grant number: TECCT11–1-0012; This work was financially supported by the Centre for the Development of Industrial Technology (CDTI) of the Spanish Ministry of Science and Innovation under grant agreement: TECNOMIFOOD project: CER-20191010; This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation, grant number: 72110. Funding Information: Acknowledgments: We gratefully acknowledge the help of Yaiza Tobajas, Anna Antol{\'i}n, Iris Triguero, Cristina Egea and Gertruda Chomiciute, who are laboratory technicians at the Technological Unit of Nutrition and Health of Eurecat, for their technical support. We thank H{\'e}ctor Palacios and Miguel {\'A}ngel Rodriguez, who are researchers at the Centre for Omic Sciences (Joint Unit Eurecat-Universitat Rovira i Virgili), for their support in the NMR analysis. The authors would like to thank NGI Sweden for generation of transcriptomics data. AM and HY acknowledge support from the PoLiMeR Innovative Training Network (Marie Sk{\l}odowska-Curie Grant Agreement No. 812616), which has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme. We thank Cambridge Commodities and ChromaDex for providing the ingredients of the mul-ti-ingredient. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project SNIC 2020/16-69. J.M.-P is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP18/00009), co-funded by the European Social Fund “Investing in your future”. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = oct,

doi = "10.3390/biomedicines9101440",

language = "English",

volume = "9",

journal = "Biomedicines",

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T1 - Combined metabolic activators decrease liver steatosis by activating mitochondrial metabolism in hamsters fed with a high-fat diet

AU - Yang, Hong

AU - Mayneris-Perxachs, Jordi

AU - Boqué, Noemí

AU - Del Bas, Josep M.

AU - Arola, Lluís

AU - Yuan, Meng

AU - Türkez, Hasan

AU - Uhlén, Mathias

AU - Borén, Jan

AU - Zhang, Cheng

AU - Mardinoglu, Adil

AU - Caimari, Antoni

N1 - Funding Information: This research was funded by the Agency for Business Competitiveness of the Government of Catalonia (ACCI?), grant number: TECCT11?1-0012; This work was financially supported by the Centre for the Development of Industrial Technology (CDTI) of the Spanish Ministry of Science and Innovation under grant agreement: TECNOMIFOOD project: CER-20191010; This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation, grant number: 72110. Funding Information: Funding: This research was funded by the Agency for Business Competitiveness of the Government of Catalonia (ACCIÓ), grant number: TECCT11–1-0012; This work was financially supported by the Centre for the Development of Industrial Technology (CDTI) of the Spanish Ministry of Science and Innovation under grant agreement: TECNOMIFOOD project: CER-20191010; This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation, grant number: 72110. Funding Information: Acknowledgments: We gratefully acknowledge the help of Yaiza Tobajas, Anna Antolín, Iris Triguero, Cristina Egea and Gertruda Chomiciute, who are laboratory technicians at the Technological Unit of Nutrition and Health of Eurecat, for their technical support. We thank Héctor Palacios and Miguel Ángel Rodriguez, who are researchers at the Centre for Omic Sciences (Joint Unit Eurecat-Universitat Rovira i Virgili), for their support in the NMR analysis. The authors would like to thank NGI Sweden for generation of transcriptomics data. AM and HY acknowledge support from the PoLiMeR Innovative Training Network (Marie Skłodowska-Curie Grant Agreement No. 812616), which has received funding from the European Union’s Horizon 2020 research and innovation programme. We thank Cambridge Commodities and ChromaDex for providing the ingredients of the mul-ti-ingredient. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project SNIC 2020/16-69. J.M.-P is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP18/00009), co-funded by the European Social Fund “Investing in your future”. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/10

Y1 - 2021/10

N2 - Although the prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase, there is no effective treatment approved for this condition. We previously showed, in high-fat diet (HFD)-fed mice, that the supplementation of combined metabolic activators (CMA), including nicotinamide riboside (NAD+ precursor) and the potent glutathione precursors serine and N-acetyl-l-cysteine (NAC), significantly decreased fatty liver by promoting fat oxidation in mitochondria. Afterwards, in a one-day proof-of-concept human supplementation study, we observed that this CMA, including also L-carnitine tartrate (LCT), resulted in increased fatty acid oxidation and de novo glutathione synthesis. However, the underlying molecular mechanisms associated with sup-plementation of CMA have not been fully elucidated. Here, we demonstrated in hamsters that the chronic supplementation of this CMA (changing serine for betaine) at two doses significantly decreased hepatic steatosis. We further generated liver transcriptomics data and integrated these data using a liver-specific genome-scale metabolic model of liver tissue. We systemically determined the molecular changes after the supplementation of CMA and found that it activates mitochondria in the liver tissue by modulating global lipid, amino acid, antioxidant and folate metabolism. Our findings provide extra evidence about the beneficial effects of a treatment based on this CMA against NAFLD.

AB - Although the prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase, there is no effective treatment approved for this condition. We previously showed, in high-fat diet (HFD)-fed mice, that the supplementation of combined metabolic activators (CMA), including nicotinamide riboside (NAD+ precursor) and the potent glutathione precursors serine and N-acetyl-l-cysteine (NAC), significantly decreased fatty liver by promoting fat oxidation in mitochondria. Afterwards, in a one-day proof-of-concept human supplementation study, we observed that this CMA, including also L-carnitine tartrate (LCT), resulted in increased fatty acid oxidation and de novo glutathione synthesis. However, the underlying molecular mechanisms associated with sup-plementation of CMA have not been fully elucidated. Here, we demonstrated in hamsters that the chronic supplementation of this CMA (changing serine for betaine) at two doses significantly decreased hepatic steatosis. We further generated liver transcriptomics data and integrated these data using a liver-specific genome-scale metabolic model of liver tissue. We systemically determined the molecular changes after the supplementation of CMA and found that it activates mitochondria in the liver tissue by modulating global lipid, amino acid, antioxidant and folate metabolism. Our findings provide extra evidence about the beneficial effects of a treatment based on this CMA against NAFLD.

KW - Combined metabolic activators

KW - Mitochondrial metabolism

KW - NAFLD

KW - Transcriptomics

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DO - 10.3390/biomedicines9101440

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JO - Biomedicines

JF - Biomedicines

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M1 - 1440

ER -

Combined metabolic activators decrease liver steatosis by activating mitochondrial metabolism in hamsters fed with a high-fat diet

Abstract

Keywords

UN SDGs

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