Lactate-Induced Lipid Accumulation in Hepatocytes through GPR81 Activation (Diabetes Metab J 2026;50:307-19)

Baodong Wang; Jiayuan Huang; Zhiyun Chen

doi:10.4093/dmj.2025.1249

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Letter Lactate-Induced Lipid Accumulation in Hepatocytes through GPR81 Activation (Diabetes Metab J 2026;50:307-19): Baodong Wang^1*, Jiayuan Huang^2*, Zhiyun Chen¹; Diabetes & Metabolism Journal 2026;50(3):618-620.
DOI: https://doi.org/10.4093/dmj.2025.1249
Published online: April 30, 2026

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¹Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China

²Department of Massage, Hangzhou Integrative Medicine Hospital Affiliated to Zhejiang Chinese Medical University (Hangzhou Red Cross Hospital), Hangzhou, China

Corresponding author: Zhiyun Chen

The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China E-mail: jcyjzxchen@163.com

*Baodong Wang and Jiayuan Huang contributed equally to this study as first authors.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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See the reply "Lactate-Induced Lipid Accumulation in Hepatocytes through GPR81 Activation (Diabetes Metab J 2026;50: 307-19)" in Volume 50 on page 623.

See the article "Lactate-Induced Lipid Accumulation in Hepatocytes through GPR81 Activation" on page 307.

Nguyen et al. [1] combine alpha mouse liver 12 (AML12) hepatocytes, nonalcoholic fatty liver disease (NAFLD) mouse models, and a zebrafish system to argue that lactate promotes hepatic steatosis through G-protein-coupled receptor 81 (GPR81)-dependent inhibition of AMP-activated protein kinase (AMPK). In vitro, AML12 cells exposed to 20 or 40 mmol/L L-lactate for 4 days accumulated triglycerides without loss of viability, with Oil Red O and biochemical assays showing increased lipid content. In vivo, 12 weeks of high-fat diet (HFD) or high-fat high-cholesterol (HFHC) feeding elevated hepatic lactate and GPR81 expression, while 10 mmol/L lactate for 24 hours increased liver lipids in fabp10a: cyan fluorescent protein (CFP) zebrafish larvae. Notably, hepatic p-AMPK fell in HFD livers but rose in HFHC livers despite consistently elevated GPR81 expression. Together, these data reposition lactate from a glycolytic by-product to a context-dependent signal in NAFLD. We suggest several refinements that may sharpen its translational interpretation [1].

First, the chronic lactate exposure protocol in AML12 cells may overstate the degree and stability of lactatemia expected in most patients. The authors used continuous 20 to 40 mmol/L lactate for 4 days [1]. By contrast, fasting and post-prandial lactate typically fluctuate within the low-millimolar range [2]. It would therefore be informative to complement the current design with ‘lactate clamp’ experiments at high-normal concentrations and with intermittent pulses synchronized to nutrient availability. Such protocols could clarify whether the increase in triglycerides observed at 20 to 40 mmol/L represents an amplification of a physiological signal or a qualitatively distinct toxic milieu.

Second, the divergence of AMPK signaling between models suggests a richer topography than a simple linear ‘lactate→GPR81→AMPK off→steatosis’ pathway. In AML12 cells, the authors show that lactate reduces p-AMPK and that GPR81 knockdown restores phosphorylation and attenuates lipogenesis, while pharmacologic AMPK activation with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reverses lactate-induced lipid accumulation [1]. In vivo, p-AMPK decreases in HFD livers but increases in HFHC livers, even though both diets raise hepatic lactate and GPR81 [1]. One way to reconcile these findings is to move from a global to a compartment-specific view of AMPK [3]. GPR81 might preferentially modulate peri-lipid droplet or plasma-membrane AMPK pools that favor lipogenesis and fatty-acid uptake, while HFHC feeding engages other kinases and phosphatases that activate AMPK pools linked to oxidative or stress-adaptive programs. Phosphoproteomics or proximity-labeling focused on liver kinase B1 (LKB1), calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), and transforming growth factor beta-activated kinase 1 (TAK1)-dependent AMPK nodes could test whether ‘lipogenic AMPK’ is selectively suppressed while other AMPK functions remain intact [4,5].

Third, the study invites integration of receptor-mediated GPR81 signaling with emerging work on lactate as an epigenetic modifier. The authors show that GPR81 knockdown normalizes AMPK phosphorylation and reduces expression of lipogenic genes, and they report that lactate increases monocarboxylate transporter 1 (MCT1) and GPR81 expression, and that GPR81 knockdown reduces MCT1 levels, although pharmacologic MCT1 inhibition did not attenuate lipid accumulation, suggesting that GPR81 rather than MCT1 is the dominant driver in this setting [1]. Yet lactate can also serve as a substrate for histone lysine lactylation, which activates metabolic and inflammatory transcriptional programs [6]. In this system, it would be informative to ask whether prolonged exposure to lactate not only alters AMPK activity but also imprints a ‘lactate signature’ on chromatin at loci such as sterol regulatory element binding transcription factor 1 (Srebf1), fatty acid synthase (Fasn), and stearoyl-CoA desaturase 1 (Scd1). Chromatin immunoprecipitation for lactylated histone marks, or epigenomic profiling under chronic low-millimolar versus high-millimolar lactate, could reveal whether GPR81-dependent and receptor-independent layers of lactate biology converge on the same lipogenic network or act in parallel.

Finally, the translational implications of targeting GPR81 in NAFLD merit cautious framing. In the HFD and HFHC mouse models, increased hepatic GPR81 expression tracks with lactate accumulation and steatosis [1]. Based largely on in vitro hepatocyte siRNA data, genetic or pharmacologic disruption of this axis appears attractive [1]. However, GPR81 is also highly expressed in adipocytes, where it couples lactate to suppression of lipolysis, and is detectable in immune cells [7,8]. A systemic GPR81 antagonist might therefore relieve hepatic lipid burden at the cost of increased circulating non-esterified fatty acids, altered adipose tissue remodeling, or effects on tumor and immune microenvironments where lactate-GPR81 signaling has been implicated [8,9]. The zebrafish experiments further indicate that lactate can remodel lipid distribution across tissues [1]. We would thus advocate for strategies that favor tissue-selective or ligand-biased modulation of GPR81, perhaps guided by metabolic phenotyping to identify patient endotypes in whom hepatic GPR81 signaling is a dominant driver rather than an adaptive response.

In summary, Nguyen et al. [1] provide compelling evidence that lactate, acting through GPR81 and AMPK, can promote hepatocellular lipid accumulation in vitro and in vivo. By refining the exposure paradigm to better mirror human lactate dynamics, dissecting compartment-specific AMPK circuits, and incorporating epigenetic and systemic perspectives, future work could determine when lactate-GPR81 signaling is truly pathogenic and when it reflects a compensatory adjustment to nutrient excess. Such contextual insight will be important if this mechanistic axis is to be translated into safe and effective therapies for NAFLD, a disease shaped as much by whole-body metabolic flux as by hepatocyte lipid storage alone.

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CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS

Generative AI (ChatGPT) was used solely to review and improve language clarity. All scientific content and interpretations are the authors’ own work.

REFERENCES

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5. Yan Y, Li M, Lin J, Ji Y, Wang K, Yan D, et al. Adenosine monophosphate activated protein kinase contributes to skeletal muscle health through the control of mitochondrial function. Front Pharmacol 2022;13:947387.Article PubMed PMC
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8. Ahmed K, Tunaru S, Tang C, Muller M, Gille A, Sassmann A, et al. An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81. Cell Metab 2010;11:311-9.Article PubMed
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Lactate-Induced Lipid Accumulation in Hepatocytes through GPR81 Activation (Diabetes Metab J 2026;50:307-19)

Diabetes Metab J. 2026;50(3):618-620. Published online April 30, 2026

DOI: https://doi.org/10.4093/dmj.2025.1249

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Lactate-Induced Lipid Accumulation in Hepatocytes through GPR81 Activation (Diabetes Metab J 2026;50:307-19)

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Wang B, Huang J, Chen Z. Lactate-Induced Lipid Accumulation in Hepatocytes through GPR81 Activation (Diabetes Metab J 2026;50:307-19). Diabetes Metab J. 2026;50(3):618-620.

DOI: https://doi.org/10.4093/dmj.2025.1249.

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