Shaina Gomez

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects roughly one-third of adults globally and carries strong associations with obesity, insulin resistance, and type 2 diabetes.^¹ Rather than a simple problem of fat storage, MASLD is increasingly understood as a progressive metabolic disease shaped by dysregulated transcription, heightened de novo lipogenesis, impaired lipid handling, and direct hepatocellular damage.^² Despite growing recognition of these mechanisms, the specific molecular regulators that drive the transition from benign steatosis to fibrosis remain incompletely defined. TCF7L2, a transcription factor operating within the Wnt/β-catenin signaling pathway, has recently been identified as a key organizer of hepatic metabolism and a plausible driver of MASLD progression.^³˒⁴

Objective: This narrative review examines the mechanisms through which hepatocyte TCF7L2 maintains normal hepatic metabolic function and explores how its loss may promote MASLD development and progression.

Search Methods: PubMed was searched for articles published between 2017 and 2023 using the following MeSH terms and keywords: “TCF7L2,” “MASLD,” “NAFLD,” “hepatic lipogenesis,” “metabolic zonation,” “de novo lipogenesis,” “liver fibrosis,” and “Wnt signaling liver.”

Results: TCF7L2 plays a central role in maintaining pericentral metabolic zonation, the spatial organization of hepatocyte gene expression across the liver lobule that allows different zones to carry out distinct metabolic tasks.⁸ When hepatocyte TCF7L2 is lost, this architecture breaks down, altering cholesterol and bile acid metabolism and triggering early fibrotic changes even in the absence of significant inflammation.⁸ These findings raise the possibility that disrupted metabolic organization alone is sufficient to initiate fibrogenesis. TCF7L2 also acts as a brake on de novo lipogenesis, as hepatocyte-specific knockout models show marked upregulation of lipogenic transcription factors including SREBP-1c and ChREBP, along with substantially increased fatty acid synthesis.⁴ Importantly, restoring TCF7L2 expression reduces steatosis and brings triglyceride levels back toward normal, directly linking TCF7L2 loss to hepatic lipid accumulation.⁴ A separate mechanism involves HACD3, a fatty acid elongase that TCF7L2 normally represses. When TCF7L2 activity is reduced, HACD3 is released, driving fatty acid elongation, endoplasmic reticulum stress, and hepatocellular injury.⁵ TCF7L2’s influence also extends to the gut-liver axis, where it regulates intestinal FGF15 signaling to modulate bile acid synthesis and lipid absorption.⁶ Additionally, TCF7L2 organizes hepatic glutamine and amino acid metabolism, supporting the liver’s ability to adapt under nutritional stress, a role further supported by human genetic data linking TCF7L2 variants to altered glutamine levels and metabolic susceptibility.⁷

Conclusion: Taken together, these findings cast TCF7L2 as a broad transcriptional coordinator of hepatic metabolism, with roles spanning lipid synthesis, spatial metabolic organization, lipotoxic protection, gut-liver communication, and amino acid handling. Loss of TCF7L2 function appears to destabilize multiple interconnected pathways simultaneously, accelerating progression from early steatosis toward fibrosis. TCF7L2 and its downstream effectors therefore represent compelling candidates for both early biomarker development and targeted therapy in MASLD. Whether pharmacologic restoration of TCF7L2 activity can slow or reverse fibrotic progression remains an important open question for future investigation.

Works Cited

1. Tilg H, Petta S, Stefan N, Targher G. Metabolic dysfunction–associated steatotic liver disease in adults: a review. JAMA. 2026;335(2):163-174. doi:10.1001/jama.2025.19615
2. Nassir F. NAFLD: mechanisms, treatments, and biomarkers. Biomolecules. 2022;12(6):824. doi:10.3390/biom12060824
3. Tanase DM, Gosav EM, Costea CF, et al. The intricate relationship between type 2 diabetes mellitus, insulin resistance, and nonalcoholic fatty liver disease. J Diabetes Res. 2020;2020:3920196. doi:10.1155/2020/3920196
4. Lee DS, An TH, Kim H, et al. Tcf7l2 in hepatocytes regulates de novo lipogenesis in diet-induced non-alcoholic fatty liver disease in mice. Diabetologia. 2023;66(5):931-954. doi:10.1007/s00125-023-05878-8
5. Mondal A, Nandi S, Singh V, et al. TCF7l2 regulates fatty acid chain elongase HACD3 during lipid-induced stress. Biochemistry. 2025;64(8):1828-1840. doi:10.1021/acs.biochem.4c00491
6. Bhat N, Esteghamat F, Chaube BK, et al. TCF7L2 transcriptionally regulates Fgf15 to maintain bile acid and lipid homeostasis through gut liver crosstalk. FASEB J. 2022;36(3):e22185. doi:10.1096/fj.202101607R
7. Krawczyk J, O’Connor W, Vendramini P, et al. The diabetes gene Tcf7l2 organizes gene expression in the liver and regulates amino acid metabolism. Mol Metab. 2025;99:102208. doi:10.1016/j.molmet.2025.102208
8. Ayala I, Hebbale SK, Mononen J, et al. The spatial transcriptional activity of hepatic TCF7L2 regulates zonated metabolic pathways that contribute to liver fibrosis. Nat Commun. 2025;16(1):3408. doi:10.1038/s41467-025-58714-5