Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients

Mujdat Zeybel; Ozlem Altay; Muhammad Arif; Xiangyu Li; Hong Yang; Claudia Fredolini; Murat Akyildiz; Burcin Saglam; Mehmet Gokhan Gonenli; Dilek Ural; Woonghee Kim; Jochen M. Schwenk; Cheng Zhang; Saeed Shoaie; Jens Nielsen; Mathias Uhlén; Jan Borén; Adil Mardinoglu

doi:10.15252/msb.202110459

Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients

Mujdat Zeybel, Ozlem Altay, Muhammad Arif, Xiangyu Li, Hong Yang, Claudia Fredolini, Murat Akyildiz, Burcin Saglam, Mehmet Gokhan Gonenli, Dilek Ural, Woonghee Kim, Jochen M. Schwenk, Cheng Zhang, Saeed Shoaie, Jens Nielsen, Mathias Uhlén, Jan Borén, Adil Mardinoglu^*

^*Corresponding author for this work

Centre for Host Microbiome Interactions

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

24 Citations (Scopus)

Abstract

Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host–microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients.

Original language	English
Article number	e10459
Journal	Molecular Systems Biology
Volume	17
Issue number	10
DOIs	https://doi.org/10.15252/msb.202110459
Publication status	Published - Oct 2021

Keywords

CMA
multi-omics
NAFLD
systems biology

UN SDGs

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

Access to Document

10.15252/msb.202110459

Cite this

Zeybel, M., Altay, O., Arif, M., Li, X., Yang, H., Fredolini, C., Akyildiz, M., Saglam, B., Gonenli, M. G., Ural, D., Kim, W., Schwenk, J. M., Zhang, C., Shoaie, S., Nielsen, J., Uhlén, M., Borén, J., & Mardinoglu, A. (2021). Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients. Molecular Systems Biology, 17(10), Article e10459. https://doi.org/10.15252/msb.202110459

@article{e48abd2aa34343c78d31ff72da7f11bd,

title = "Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients",

abstract = "Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host–microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients.",

keywords = "CMA, multi-omics, NAFLD, systems biology",

author = "Mujdat Zeybel and Ozlem Altay and Muhammad Arif and Xiangyu Li and Hong Yang and Claudia Fredolini and Murat Akyildiz and Burcin Saglam and Gonenli, {Mehmet Gokhan} and Dilek Ural and Woonghee Kim and Schwenk, {Jochen M.} and Cheng Zhang and Saeed Shoaie and Jens Nielsen and Mathias Uhl{\'e}n and Jan Bor{\'e}n and Adil Mardinoglu",

note = "Funding Information: This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation (Grant no. 72110). The authors would like to thank ChromaDex (Irvine, CA, USA) for providing NR for this study, to the Plasma Profiling Facility team at SciLifeLab in Stockholm for generating the Olink data, Metabolon Inc. (Durham, USA) for the generation of metabolomic data and NGI Sweden for the generation of metagenomic data. The authors gratefully acknowledge the use of the services and facilities of the Ko{\c c} University Research Center for Translational Medicine (KUTTAM), equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. Findings, opinions, or points of view expressed in this article do not necessarily represent the official position or policies of the Ministry of Development. HY and AM acknowledge support from the PoLiMeR Innovative Training Network (Marie Sklodowska‐Curie Grant Agreement No. 812616) which has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project SNIC 2020/16‐69. Funding Information: This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation (Grant no. 72110). The authors would like to thank ChromaDex (Irvine, CA, USA) for providing NR for this study, to the Plasma Profiling Facility team at SciLifeLab in Stockholm for generating the Olink data, Metabolon Inc. (Durham, USA) for the generation of metabolomic data and NGI Sweden for the generation of metagenomic data. The authors gratefully acknowledge the use of the services and facilities of the Ko? University Research Center for Translational Medicine (KUTTAM), equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. Findings, opinions, or points of view expressed in this article do not necessarily represent the official position or policies of the Ministry of Development. HY and AM acknowledge support from the PoLiMeR Innovative Training Network (Marie Sklodowska-Curie Grant Agreement No. 812616) which has received funding from the European Union?s Horizon 2020 research and innovation program. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project SNIC 2020/16-69. Publisher Copyright: {\textcopyright} 2021 The Authors. Published under the terms of the CC BY 4.0 license.",

year = "2021",

month = oct,

doi = "10.15252/msb.202110459",

language = "English",

volume = "17",

journal = "Molecular Systems Biology",

issn = "1744-4292",

publisher = "Wiley-Blackwell",

number = "10",

}

Zeybel, M, Altay, O, Arif, M, Li, X, Yang, H, Fredolini, C, Akyildiz, M, Saglam, B, Gonenli, MG, Ural, D, Kim, W, Schwenk, JM, Zhang, C, Shoaie, S, Nielsen, J, Uhlén, M, Borén, J & Mardinoglu, A 2021, 'Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients', Molecular Systems Biology, vol. 17, no. 10, e10459. https://doi.org/10.15252/msb.202110459

TY - JOUR

T1 - Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients

AU - Zeybel, Mujdat

AU - Altay, Ozlem

AU - Arif, Muhammad

AU - Li, Xiangyu

AU - Yang, Hong

AU - Fredolini, Claudia

AU - Akyildiz, Murat

AU - Saglam, Burcin

AU - Gonenli, Mehmet Gokhan

AU - Ural, Dilek

AU - Kim, Woonghee

AU - Schwenk, Jochen M.

AU - Zhang, Cheng

AU - Shoaie, Saeed

AU - Nielsen, Jens

AU - Uhlén, Mathias

AU - Borén, Jan

AU - Mardinoglu, Adil

N1 - Funding Information: This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation (Grant no. 72110). The authors would like to thank ChromaDex (Irvine, CA, USA) for providing NR for this study, to the Plasma Profiling Facility team at SciLifeLab in Stockholm for generating the Olink data, Metabolon Inc. (Durham, USA) for the generation of metabolomic data and NGI Sweden for the generation of metagenomic data. The authors gratefully acknowledge the use of the services and facilities of the Koç University Research Center for Translational Medicine (KUTTAM), equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. Findings, opinions, or points of view expressed in this article do not necessarily represent the official position or policies of the Ministry of Development. HY and AM acknowledge support from the PoLiMeR Innovative Training Network (Marie Sklodowska‐Curie Grant Agreement No. 812616) which has received funding from the European Union’s Horizon 2020 research and innovation program. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project SNIC 2020/16‐69. Funding Information: This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation (Grant no. 72110). The authors would like to thank ChromaDex (Irvine, CA, USA) for providing NR for this study, to the Plasma Profiling Facility team at SciLifeLab in Stockholm for generating the Olink data, Metabolon Inc. (Durham, USA) for the generation of metabolomic data and NGI Sweden for the generation of metagenomic data. The authors gratefully acknowledge the use of the services and facilities of the Ko? University Research Center for Translational Medicine (KUTTAM), equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. Findings, opinions, or points of view expressed in this article do not necessarily represent the official position or policies of the Ministry of Development. HY and AM acknowledge support from the PoLiMeR Innovative Training Network (Marie Sklodowska-Curie Grant Agreement No. 812616) which has received funding from the European Union?s Horizon 2020 research and innovation program. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project SNIC 2020/16-69. Publisher Copyright: © 2021 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2021/10

Y1 - 2021/10

N2 - Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host–microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients.

AB - Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host–microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients.

KW - CMA

KW - multi-omics

KW - NAFLD

KW - systems biology

UR - http://www.scopus.com/inward/record.url?scp=85118224284&partnerID=8YFLogxK

U2 - 10.15252/msb.202110459

DO - 10.15252/msb.202110459

M3 - Article

AN - SCOPUS:85118224284

SN - 1744-4292

VL - 17

JO - Molecular Systems Biology

JF - Molecular Systems Biology

IS - 10

M1 - e10459

ER -

Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this