{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T01:27:20Z","timestamp":1783042040568,"version":"3.54.6"},"reference-count":30,"publisher":"Korean Diabetes Association","issue":"2","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["e-dmj.org"],"crossmark-restriction":true},"short-container-title":["Diabetes Metab J"],"published-print":{"date-parts":[[2026,3,1]]},"abstract":"<jats:p>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 &lt;i&gt;in vitro&lt;\/i&gt; 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\u2019 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 &lt;i&gt;de novo&lt;\/i&gt; 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\u2013AMPK 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.<\/jats:p>","DOI":"10.4093\/dmj.2024.0531","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T05:16:53Z","timestamp":1764220613000},"page":"307-319","update-policy":"https:\/\/doi.org\/10.4093\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Lactate-Induced Lipid Accumulation in Hepatocytes through GPR81 Activation"],"prefix":"10.4093","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9269-262X","authenticated-orcid":true,"given":"Giang","family":"Nguyen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1907-2859","authenticated-orcid":true,"given":"Ji Hee","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuc Thi 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