Diabetes & Metabolism Journal

Original Articles

Basic and Translational Research
Lactate-Induced Lipid Accumulation in Hepatocytes through GPR81 Activation: Giang Nguyen, Ji Hee Yu, Phuc Thi Minh Pham, Thuy Linh Lai, So Young Park, Ki Woo Kim, Seung-Soon Im, Jeana Hong, Yong-ho Lee, Jae-Ho Lee, Seon Mee Kang, Dae-Hee Choi, Eun-Hee Cho; Diabetes Metab J. 2026;50(2):307-319. Published online November 27, 2025; DOI: https://doi.org/10.4093/dmj.2024.0531

3,719 View
182 Download
3 Web of Science
1 Crossref

Abstract PDF Supplementary Material PubReader ePub

Background
Lactate, traditionally considered a metabolic byproduct, is increasingly recognized as a signaling molecule involved in metabolic regulation. Its role in hepatic steatosis, particularly through G-protein-coupled receptor 81 (GPR81)-mediated pathways, remains underexplored.
Methods
We investigated the effects of lactate on hepatic lipid metabolism using in vitro alpha mouse liver 12 (AML12) cells, zebrafish, and two diet-induced nonalcoholic fatty liver disease (NAFLD) mouse models. Lipid accumulation, gene/protein expression, and 5’ adenosine monophosphate-activated protein kinase (AMPK) signaling were assessed under lactate exposure, GPR81 knockdown, monocarboxylate transporter 1 (MCT1) inhibition, and AMPK activation conditions.
Results
Lactate treatment in hepatocytes increased de novo lipogenesis and fatty acid uptake while suppressing fatty acid oxidation and AMPK phosphorylation. These effects were reversed by GPR81 knockdown but not by MCT1 inhibition, suggesting a GPR81-dependent mechanism. AMPK activation with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reduced lactate-induced lipid accumulation. In zebrafish, 10 mM lactate treatment for 24 hours significantly increased hepatic lipid content. In mice fed high-fat diet (HFD) or high-fat high-cholesterol (HFHC) diets for 12 weeks, hepatic lactate levels and GPR81 expression were elevated. Interestingly, p-AMPK expression decreased in HFD livers but increased in the HFHC group, indicating dietspecific regulation.
Conclusion
Our findings demonstrate that lactate promotes hepatic steatosis primarily via the GPR81–AMPK signaling axis. GPR81 activation enhances lipogenesis and lipid uptake, independent of MCT1-mediated transport. These results position GPR81 as a promising therapeutic target for NAFLD.

Citations

Citations to this article as recorded by

LncRNA LELE enhances lactate efflux and reduces lipid deposition via upregulating MCT1
Kang Xiao, Yingying Zhou, Qiyong Qiu, Chenguang Zhu, Xiaoxue Shen, Le Chang, Wei Qiang, Hengtong Liu, Guangzhen Jiang, Xiangfei Li, Wenbin Liu, Dingdong Zhang
Aquaculture.2026; 622: 744043. CrossRef

Pathophysiology
Enavogliflozin, an SGLT2 Inhibitor, Improves Nonalcoholic Steatohepatitis Induced by High-Fat, High-Cholesterol Diet: Phuc Thi Minh Pham, Giang Nguyen, So Young Park, Thuy Linh Lai, Dae-Hee Choi, Jeana Hong, Seon Mee Kang, Eun-Hee Cho; Diabetes Metab J. 2026;50(1):165-177. Published online June 16, 2025; DOI: https://doi.org/10.4093/dmj.2024.0259

5,091 View
176 Download
4 Web of Science
3 Crossref

Abstract PDF Supplementary Material PubReader ePub

Background
Nonalcoholic fatty liver disease, a progressive condition caused by the accumulation of fat in the liver, begins with simple steatosis and can potentially progress to metabolic dysfunction-associated steatohepatitis (MASH) in the presence of inflammation and fibrosis, ultimately leading to cirrhosis or hepatocellular carcinoma. Increasing evidence indicates that sodiumglucose cotransporter 2 (SGLT2) inhibitors effectively alleviate MASH in mouse models. However, there is a lack of research on the effects of enavogliflozin on liver disease. In the present study, we investigated the effects of SGLT2 inhibitors on MASH induced by a high-fat, high-cholesterol (HFHC) diet in mice.
Methods
Male C57BL/6 mice were fed a normal chow diet, HFHC diet, or HFHC diet with enavogliflozin for 12 weeks. LX-2 and HepG2 cells were treated with enavogliflozin in the presence of various pathological stimuli.
Results
The HFHC diet induced excessive hepatic lipid accumulation, inflammation, and severe fibrosis. Administration of enavogliflozin not only ameliorated hepatic steatosis and fibrotic conditions but also suppressed the production of inflammatory cytokines. Positive outcomes were also observed in in vitro experiments, where enavogliflozin demonstrated the ability to impede the activation of hepatic stellate cells and alleviate lipid accumulation in hepatocytes. The potential pathway through which enavogliflozin attenuated liver fibrosis development may be associated with the transforming growth factor β1/Smad signaling pathway.
Conclusion
Our results suggest that enavogliflozin is effective in a mouse model of MASH by attenuating hepatic steatosis, suppressing inflammation, and improving liver fibrosis.

Citations

Citations to this article as recorded by

Signaling Pathway Remodeling and Molecular Regulation in the HCC TME: Dynamic Evolution and Clinical Therapeutic Advances
Lin Xu, Xuanhao Zhang, Hengzhou Zhu, Dong Niu, Xiaodan Zhu, Chunhui Jin
Frontiers in Bioscience-Landmark.2026;[Epub] CrossRef
Dissecting out the unexpected effects of SGLT2 inhibitors on human aging
Goro Katsuumi, Tohru Minamino
The Journal of Clinical Endocrinology & Metabolism.2026;[Epub] CrossRef
SGLT2 Inhibitors as Systemic Metabolic Modulators: Linking Glucose Excretion to Liver Function Restoration
Seung Wan Noh, Han Sol Ryu, Yong-Ho Kim, Byung-Chul Oh
Endocrinology and Metabolism.2025; 40(6): 851. CrossRef

First
Prev
Page of 1
Next
Last

Search