Lactate-Induced Lipid Accumulation in Hepatocytes through GPR81 Activation

Area of Science:

• Metabolic Regulation
• Hepatology
• Molecular Signaling

Background:

• Lactate is recognized as a signaling molecule in metabolic regulation.
• The role of lactate in hepatic steatosis via G-protein-coupled receptor 81 (GPR81) is not well understood.

Purpose of the Study:

• To investigate the effects of lactate on hepatic lipid metabolism.
• To elucidate the role of GPR81 and 5' adenosine monophosphate-activated protein kinase (AMPK) signaling in lactate-induced hepatic steatosis.

Main Methods:

• In vitro studies using AML12 cells, zebrafish, and diet-induced nonalcoholic fatty liver disease (NAFLD) mouse models.
• Assessment of lipid accumulation, gene/protein expression, and AMPK signaling.
• Experimental manipulations included lactate exposure, GPR81 knockdown, MCT1 inhibition, and AMPK activation.

Main Results:

• Lactate increased de novo lipogenesis and fatty acid uptake while decreasing fatty acid oxidation and AMPK phosphorylation in hepatocytes, mediated by GPR81.
• AMPK activation reduced lactate-induced lipid accumulation.
• Lactate treatment increased hepatic lipid content in zebrafish and elevated hepatic lactate and GPR81 in NAFLD mouse models.

Conclusions:

• Lactate promotes hepatic steatosis via the GPR81-AMPK signaling axis.
• GPR81 activation enhances lipogenesis and lipid uptake independently of MCT1.
• GPR81 represents a potential therapeutic target for NAFLD.