Lactate metabolism in human health and disease

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Abstract

The current understanding of lactate extends from its origins as a byproduct of glycolysis to its role in tumor metabolism, as identified by studies on the Warburg effect. The lactate shuttle hypothesis suggests that lactate plays an important role as a bridging signaling molecule that coordinates signaling among different cells, organs and tissues. Lactylation is a posttranslational modification initially reported by Professor Yingming Zhao’s research group in 2019. Subsequent studies confirmed that lactylation is a vital component of lactate function and is involved in tumor proliferation, neural excitation, inflammation and other biological processes. An indispensable substance for various physiological cellular functions, lactate plays a regulatory role in different aspects of energy metabolism and signal transduction. Therefore, a comprehensive review and summary of lactate is presented to clarify the role of lactate in disease and to provide a reference and direction for future research. This review offers a systematic overview of lactate homeostasis and its roles in physiological and pathological processes, as well as a comprehensive overview of the effects of lactylation in various diseases, particularly inflammation and cancer.

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A framework for advancing our understanding of cancer-associated fibroblasts

Erik Sahai, Igor Astsaturov, Edna Cukierman … (2020)

Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.

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The Warburg Effect: How Does it Benefit Cancer Cells?

Maria Liberti, Jason Locasale (2016)

Cancer cells rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance. The common feature of this altered metabolism is the increased glucose uptake and fermentation of glucose to lactate. This phenomenon is observed even in the presence of completely functioning mitochondria and, together, is known as the 'Warburg Effect'. The Warburg Effect has been documented for over 90 years and extensively studied over the past 10 years, with thousands of papers reporting to have established either its causes or its functions. Despite this intense interest, the function of the Warburg Effect remains unclear. Here, we analyze several proposed explanations for the function of Warburg Effect, emphasize their rationale, and discuss their controversies.

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Metabolic regulation of gene expression by histone lactylation

Di Zhang, Zhanyun Tang, He Huang … (2019)

The Warburg effect, originally describing augmented lactogenesis in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, macrophage polarization, and T-cell activation. This phenomenon is intimately linked with multiple diseases including neoplasia, sepsis, and autoimmune diseases 1,2 . Lactate, a compound generated during Warburg effect, is widely known as an energy source and metabolic byproduct. However, its non-metabolic functions in physiology and disease remain unknown. Here we report lactate-derived histone lysine lactylation as a new epigenetic modification and demonstrate that histone lactylation directly stimulates gene transcription from chromatin. In total, we identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce production of lactate through glycolysis that in turn serves as precursor for stimulating histone lactylation. Using bacterially exposed M1 macrophages as a model system, we demonstrate that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, elevated histone lactylation induces homeostatic genes involved in wound healing including arginase 1. Collectively, our results suggest the presence of an endogenous “lactate clock” in bacterially challenged M1 macrophages that turns on gene expression to promote homeostasis. Histone lactylation thus represents a new avenue for understanding the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.

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Author and article information

Contributors

Zhibin Wang: m17853291291@163.com

Tao Yu: yutao0112@qdu.edu.cn

Journal

Journal ID (nlm-ta): Signal Transduct Target Ther

Journal ID (iso-abbrev): Signal Transduct Target Ther

Title: Signal Transduction and Targeted Therapy

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 2095-9907

ISSN (Electronic): 2059-3635

Publication date (Electronic): 1 September 2022

Publication date PMC-release: 1 September 2022

Publication date Collection: 2022

Volume: 7

Electronic Location Identifier: 305

Affiliations

[1 ]GRID grid.412521.1, ISNI 0000 0004 1769 1119, Center for Regenerative Medicine, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University; Department of Cardiac Ultrasound, , The Affiliated Hospital of Qingdao University, ; No. 16 Jiangsu Road, Qingdao, 266000 China

[2 ]GRID grid.410645.2, ISNI 0000 0001 0455 0905, Department of Immunology, School of Basic Medicine, , Qingdao University, ; Qingdao, 266071 China

[3 ]GRID grid.415468.a, ISNI 0000 0004 1761 4893, Department of Respiratory Medicine, , Qingdao Municipal Hospital, ; Qingdao, 266011 China

[4 ]GRID grid.412521.1, ISNI 0000 0004 1769 1119, Department of Cardiac Ultrasound, , The Affiliated Hospital of Qingdao University, ; No. 16 Jiangsu Road, Qingdao, 266000 China

[5 ]GRID grid.412521.1, ISNI 0000 0004 1769 1119, Department of Cardiology, , The Affiliated Hospital of Qingdao University, ; No. 1677 Wutaishan Road, Qingdao, 266555 China

Article

Publisher ID: 1151

DOI: 10.1038/s41392-022-01151-3

PMC ID: 9434547

PubMed ID: 36050306

SO-VID: e71720d2-5026-420a-80d4-b0732b95316b

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 19 March 2022

Date revision received : 17 July 2022

Date accepted : 9 August 2022

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 81870331

Award Recipient : Tao Yu

Funded by: FundRef https://doi.org/10.13039/501100010870, Qingdao Municipal Science and Technology Bureau;

Award ID: 21-1-4-rkjk-12-nsh

Award Recipient : Tao Yu

Funded by: FundRef https://doi.org/10.13039/501100007129, Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation);

Award ID: ZR2020MH045

Award Recipient : Zhibin Wang