Diabetes & Metabolism Journal

Original Article

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.

Citations

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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

Review

Pathophysiology
Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications: Xuan Trong Truong, Dae Ho Lee; Diabetes Metab J. 2025;49(5):964-986. Published online September 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0644

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Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a progressive spectrum ranging from simple hepatic steatosis to steatohepatitis and fibrosis. Although insulin resistance (IR) plays a central role in metabolic diseases, in the liver, insulin- or substrate-driven de novo lipogenesis (DNL) promotes triglyceride accumulation through multiple complex regulatory mechanisms, including specific transcription factors, regardless of whether IR is primary or not. Elevated free fatty acids, resulting from increased adipose lipolysis, further augment hepatic lipid storage and contribute to IR and the progression of MASLD through lipotoxic intermediates such as diacylglycerols and ceramides, as well as other pathways. Numerous studies have identified DNL as a major, yet modifiable, contributor to MASLD. In addition, zonal differences in hepatic insulin signaling, non-classical insulin signaling pathways, and activation of the mechanistic target of rapamycin complex 1 and protein kinase C pathways appear to be involved in the development of selective hepatic IR. Recently, new pharmacologic agents, including resmetirom, have shown promise in improving steatohepatitis and fibrosis in MASLD. Nevertheless, sustained weight loss through lifestyle modification remains the cornerstone of MASLD prevention and therapy. Further mechanistic understanding of how IR and substrate overload promote DNL and hepatic fat accumulation is critical for developing effective treatments for MASLD.

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Original Article

Basic Research
Effects Of Exercise Training And Chlorogenic Acid Supplementation On Hepatic Lipid Metabolism In Prediabetes Mice: Samaneh Shirkhani, Sayyed Mohammad Marandi, Mohammad Hossein Nasr-Esfahani, Seung Kyum Kim; Diabetes Metab J. 2023;47(6):771-783. Published online September 8, 2023; DOI: https://doi.org/10.4093/dmj.2022.0265

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Background
Since prediabetes is a risk factor for metabolic syndromes, it is important to promote a healthy lifestyle to prevent prediabetes. This study aimed to determine the effects of green coffee (GC), chlorogenic acid (CGA) intake, and exercise training (EX) on hepatic lipid metabolism in prediabetes male C57BL/6 mice.
Methods
Forty-nine mice were randomly divided into two groups feeding with a normal diet (n=7) or a high-fat diet (HFD, n=42) for 12 weeks. Then, HFD mice were further divided into six groups (n=7/group): control (pre-D), GC, CGA, EX, GC+EX, and CGA+EX. After additional 10 weeks under the same diet, plasma, and liver samples were obtained.
Results
HFD-induced prediabetes conditions with increases in body weight, glucose, insulin, insulin resistance, and lipid profiles were alleviated in all treatment groups. Acsl3, a candidate gene identified through an in silico approach, was lowered in the pre-D group, while treatments partly restored it. HFD induced adverse alterations of de novo lipogenesis- and β oxidation-associated molecules in the liver. However, GC and CGA supplementation and EX reversed or ameliorated these changes. In most cases, GC or CGA supplementation combined with EX has no synergistic effect and the GC group had similar results to the CGA group.
Conclusion
These findings suggest that regular exercise is an effective non-therapeutic approach for prediabetes, and CGA supplementation could be an alternative to partially mimic the beneficial effects of exercise on prediabetes.

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Sulwon Lecture 2020

Pathophysiology
Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases: Inês Sousa-Lima, Hyun Jeong Kim, John Jones, Young-Bum Kim; Diabetes Metab J. 2021;45(5):655-674. Published online September 30, 2021; DOI: https://doi.org/10.4093/dmj.2021.0197

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Nonalcoholic fatty liver disease (NAFLD) is a major public health problem and the most common form of chronic liver disease, affecting 25% of the global population. Although NAFLD is closely linked with obesity, insulin resistance, and type 2 diabetes mellitus, knowledge on its pathogenesis remains incomplete. Emerging data have underscored the importance of Rho-kinase (Rho-associated coiled-coil-containing kinase [ROCK]) action in the maintenance of normal hepatic lipid homeostasis. In particular, pharmacological blockade of ROCK in hepatocytes or hepatic stellate cells prevents the progression of liver diseases such as NAFLD and fibrosis. Moreover, mice lacking hepatic ROCK1 are protected against obesity-induced fatty liver diseases by suppressing hepatic de novo lipogenesis. Here we review the roles of ROCK as an indispensable regulator of obesity-induced fatty liver disease and highlight the key cellular pathway governing hepatic lipid accumulation, with focus on de novo lipogenesis and its impact on therapeutic potential. Consequently, a comprehensive understanding of the metabolic milieu linking to liver dysfunction triggered by ROCK activation may help identify new targets for treating fatty liver diseases such as NAFLD.

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Original Article

Obesity and Metabolic Syndrome
Inhibition of Serotonin Synthesis Induces Negative Hepatic Lipid Balance: Jun Namkung, Ko Eun Shong, Hyeongseok Kim, Chang-Myung Oh, Sangkyu Park, Hail Kim; Diabetes Metab J. 2018;42(3):233-243. Published online April 25, 2018; DOI: https://doi.org/10.4093/dmj.2017.0084

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Background

Hepatic steatosis is caused by metabolic stress associated with a positive lipid balance, such as insulin resistance and obesity. Previously we have shown the anti-obesity effects of inhibiting serotonin synthesis, which eventually improved insulin sensitivity and hepatic steatosis. However, it is not clear whether serotonin has direct effect on hepatic lipid accumulation. Here, we showed the possibility of direct action of serotonin on hepatic steatosis.

Methods

Mice were treated with para-chlorophenylalanine (PCPA) or LP-533401 to inhibit serotonin synthesis and fed with high fat diet (HFD) or high carbohydrate diet (HCD) to induce hepatic steatosis. Hepatic triglyceride content and gene expression profiles were analyzed.

Results

Pharmacological and genetic inhibition of serotonin synthesis reduced HFD-induced hepatic lipid accumulation. Furthermore, short-term PCPA treatment prevented HCD-induced hepatic steatosis without affecting glucose tolerance and browning of subcutaneous adipose tissue. Gene expression analysis revealed that the expressions of genes involved in de novo lipogenesis and triacylglycerol synthesis were downregulated by short-term PCPA treatment as well as long-term PCPA treatment.

Conclusion

Short-term inhibition of serotonin synthesis prevented hepatic lipid accumulation without affecting systemic insulin sensitivity and energy expenditure, suggesting the direct steatogenic effect of serotonin in liver.

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