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PMID: 29891721 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 115 ·No. 26 ·2018-00-26 ·Pages E5896-E5905

Dai J, Liang K, Zhao S, Jia W, Liu Y, Wu H, Lv J, Cao C, Chen T, Zhuang S, Hou X, Zhou S, Zhang X, Chen XW, Huang Y, Xiao RP, Wang YL, Luo T, Xiao J, Wang C

Abstract

Obesity and related metabolic diseases are becoming worldwide epidemics that lead to increased death rates and heavy health care costs. Effective treatment options have not been found yet. Here, based on the observation that baicalin, a flavonoid from the herbal medicine Scutellaria baicalensis, has unique antisteatosis activity, we performed quantitative chemoproteomic profiling and identified carnitine palmitoyltransferase 1 (CPT1), the controlling enzyme for fatty acid oxidation, as the key target of baicalin. The flavonoid directly activated hepatic CPT1 with isoform selectivity to accelerate the lipid influx into mitochondria for oxidation. Chronic treatment of baicalin ameliorated diet-induced obesity (DIO) and hepatic steatosis and led to systemic improvement of other metabolic disorders. Disruption of the predicted binding site of baicalin on CPT1 completely abolished the beneficial effect of the flavonoid. Our discovery of baicalin as an allosteric CPT1 activator opens new opportunities for pharmacological treatment of DIO and associated sequelae.

Keywords
CPT1 baicalin chemical proteomics obesity steatosis
MeSH Terms
Allosteric Regulation/drug effects Animals Binding Sites Carnitine O-Palmitoyltransferase/metabolism Diet/adverse effects Enzyme Activation/drug effects Fatty Liver/chemically induced,enzymology,pathology,prevention & control Flavonoids/pharmacology HeLa Cells Humans Liver/enzymology,pathology Mice Mitochondria, Liver/enzymology,pathology Obesity/chemically induced,enzymology,prevention & control Proteomics
Chemicals
Flavonoids baicalin Carnitine O-Palmitoyltransferase
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
Dai Jianye ORCID
Synthetic and Functional Biomolecules Center, Peking University, 100871 Beijing, China. | Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, 100871 Beijing, China. | Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China.
Liang Kai
Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China. | School of Life Sciences, Peking University, 100871 Beijing, China.
Zhao Shan
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, 100871 Beijing, China. | Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China.
Jia Wentong
State Key Laboratory of Stem Cells and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China. | University of the Chinese Academy of Sciences, 101408 Beijing, China.
Liu Yuan
Synthetic and Functional Biomolecules Center, Peking University, 100871 Beijing, China. | Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, 100871 Beijing, China. | Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China.
Wu Hongkun
Institute of Molecular Medicine, Peking University, 100871 Beijing, China.
Lv Jia
Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China. | Institute of Molecular Medicine, Peking University, 100871 Beijing, China.
Cao Chen
College of Engineering, Peking University, 100871 Beijing, China.
Chen Tao
College of Engineering, Peking University, 100871 Beijing, China.
Zhuang Shentian
Synthetic and Functional Biomolecules Center, Peking University, 100871 Beijing, China. | Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, 100871 Beijing, China. | Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China.
Hou Xiaomeng
Synthetic and Functional Biomolecules Center, Peking University, 100871 Beijing, China. | Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, 100871 Beijing, China. | Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China.
Zhou Shijie
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, 100871 Beijing, China. | Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China.
Zhang Xiannian
College of Engineering, Peking University, 100871 Beijing, China.
Chen Xiao-Wei
Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China. | Institute of Molecular Medicine, Peking University, 100871 Beijing, China.
Huang Yanyi
Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China. | College of Engineering, Peking University, 100871 Beijing, China.
Xiao Rui-Ping
Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China. | Institute of Molecular Medicine, Peking University, 100871 Beijing, China.
Wang Yan-Ling
State Key Laboratory of Stem Cells and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China.
Luo Tuoping ORCID
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, 100871 Beijing, China. | Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China.
Xiao Junyu ORCID
Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China. | School of Life Sciences, Peking University, 100871 Beijing, China.
Wang Chu ORCID
Synthetic and Functional Biomolecules Center, Peking University, 100871 Beijing, China; [email protected]. | Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, 100871 Beijing, China. | Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China.
Conflict of Interest

The authors declare no conflict of interest.

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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1801745115
Email
[email protected]
Published
2018-00-26
Epub
2018-00-11
Pages
E5896-E5905
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC6042128
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.1801745115 PMC Full Text View journal details
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