Non-alcoholic fatty liver disease (NAFLD) is a liver disease characterized by excessive lipid deposition in the hepatocytes, independent of alcohol consumption. The global incidence of NAFLD is rising alongside increasing rates of obesity and other metabolic disorders, and it is becoming more prevalent in younger populations. Previous studies have shown that increased lactate accumulation is concomitant with the development of NAFLD.

In a recent study published in the Genes & Diseases journal, researchers from Chongqing Medical University, Western Institute of Digital-Intelligent Medicine, and the University of Chicago Medical Center provide mechanistic insights into how monocarboxylate transporter 4 (MCT4), a proton-dependent lactate transporter, influences NAFLD progression.

Initial analysis revealed that high MCT4 expression in hepatocytes correlates positively with NAFLD progression. Further experiments using syrosingopine, an MCT4 and MCT1 inhibitor, which inhibits MCT4 more efficiently than MCT1, VB124, an MCT4-specific inhibitor, and BAY-8002, an MCT1-specific inhibitor, indicated that MCT4 inhibition up-regulates the genes involved in triglyceride and fatty acid synthesis, thereby resulting in increased intracellular lipid accumulation.

Knockdown and overexpression studies showed that i) siMCT4 led to the up-regulation of genes involved in triglyceride and fatty acid synthesis and the down-regulation of genes related to their catabolism, while ii) overexpression of MCT4 exerted the opposite effect. These findings show that MCT4 silencing enhances lipid accumulation, whereas exogenous MCT4 reduces lipid accumulation in hepatocytes, suggesting a protective role for MCT4 in the progression of hepatic steatosis.

In vivo studies demonstrated that exogenous MCT4 down-regulates the expression of numerous lipolysis and lipogenesis genes related to triglycerides and fatty acids, accompanied by a concomitant decrease in intrahepatic free fatty acid, glucose, and lactate levels and increased pyruvate levels. These results strongly suggest that overexpression of MCT4 may inhibit hepatic steatosis by down-regulating hepatic lipid metabolism-related genes.

mRNA-sequencing transcriptomic analyses of MCT4-overexpressed or MCT4-silenced (siMCT4) hepatocytes showed that MCT4 regulated PPAR, HIF-1, TNF, IL-17, PI3K-AKT, Wnt, and JAK-STAT signaling pathways, as well as multiple inflammation-related biological processes by regulating the interaction of multiple hub genes, such as Arg2, Mmp8, Spp1, Apoe, Olr1, Cd74, and Irf7. Of these, Arg2 was established as a critical regulator that reduces hepatic and peripheral lipid accumulation and the hepatic inflammatory response. Taken together, these findings suggest that MCT4 suppresses hepatic steatosis and alleviates NAFLD “by driving multiple genes interactions that regulate hepatic lipid metabolism and inflammatory responses.”
In conclusion, the findings of this study show that exogenous MCT4 may mitigate hepatic steatosis, thereby ultimately attenuating NAFLD and “delineate the potential functions and mechanisms of MCT4 in NAFLD and provide novel insights into the clinical perspectives of NAFLD treatment.”

Reference

Title of the original paper: Lactate transporter MCT4 regulates the hub genes for lipid metabolism and inflammation to attenuate intracellular lipid accumulation in non-alcoholic fatty liver disease

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101554

Funding Information:

Natural Science Foundation of China (No. 82102696)
Chongqing Natural Science Foundation of China (No. 2024NSCQ-MSX0073)
US National Institutes of Health (No. CA226303)
The University of Chicago Cancer Center Support Grant (No. P30CA014599)
National Center for Advancing Translational Sciences of the US National Institutes of Health (No. UL1 TR000430).

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 7.3 | Impact Factor: 6.9

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