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

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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.

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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

Common Genetic Polymorphisms in the Promoter of Resistin Gene are Major Determinants of Plasma Resistin Concentrations in Humans.: Young Min Cho, Byung Soo Youn, Sung Soo Chung, Ki Woo Kim, Bo Kyeong Koo, Kang Yeol Yu, Hong Je Park, Hyoung Doo Shin, Hak Chul Jang, Kyong Soo Park, Seong Yeon Kim, Hong Kyu Lee; Korean Diabetes J. 2004;28(1):9-19. Published online February 1, 2004

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Abstract PDF: BACKGROUND
Resistin has been postulated to be an important link between obesity and insulin resistance. Genetic polymorphisms in the resistin gene promotor have been suggested as a determinant of the expression of resistin mRNA, which is possibly associated with obesity and insulin resistance. In this study, the association between the genotype of the resistin promoter, and its plasma concentrations, were investigated. METHODS: The g.-537A>C and g.-420C>G polymorphisms in the resistin promoter were examined, and the levels of plasma resistin measured in the Korean subjects, both with and without type 2 diabetes. Haplotype-based promoter activity and the gel electrophoretic mobility-shift assays(EMSA) were also performed. RESULTS: The -420G and the -537A alleles, which were in linkage disequilibrium, were associated with higher plasma resistin concentrations. Individuals with the A-G(-537 A and -420G) haplotypes showed significantly higher plasma resistin levels than those that did not. The haplotypes A-G had modestly increased promoter activities compared to the other haplotypes. The EMSA revealed the -420 G allele to be specific for binding of the nuclear proteins from adipocytes and monocytes. However, neither polymorphism was associated with type 2 diabetes or obesity in our study subjects. CONCLUSION: Polymorphisms in the promoter of the resistin gene are major determinants of plasma resistin concentrations in humans

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