Transcription factor 19 modulates fatty acid elongation and unfolded protein response to attenuate palmitic acid-induced hepatic dysfunction

Mondal et al., Nature Communications, 2026 asked how a liver cell copes when it is handed more saturated fat than it can burn, and whether the transcription factor TCF19 is what lets it cope. The team combined lipidomics, transcriptomics and chromatin work in human hepatoma lines with two mouse models and human liver samples, and reported that TCF19 turns on the fatty acid elongation enzymes ELOVL1 and HACD3 and the protein refolding enzyme PDIA4, so that excess free fatty acid is packed into triglyceride and stored rather than left loose in the cell.

The loss of function arm in the animals was carried by AUMsilence sdASO against mouse Tcf19. In the first model, 6 week old BALB/c mice received palmitic acid conjugated to BSA by tail vein twice a day for 7 days, and the oligonucleotide was injected at 10 mg per Kg body weight every 2 days. In the second, mice were fed a diet of 60% fat as palmitic acid for 3 months and the same oligonucleotide was given at the same dose every 2 days through the final month. The same sequence silenced Tcf19 in primary mouse hepatocytes, with no carrier named for it, while the two plasmid constructs described in the same paragraph both name a transfection reagent. The knockdown work in the human HepG2 and Huh7 lines used a plasmid shRNA construct and is a separate arm of the study.

Silencing Tcf19 in the palmitic acid mice altered the liver pool of very long chain fatty acids and cut serum triglyceride. ELOVL1 and HACD3 protein, raised by palmitic acid, came back down in the silenced tissue, and PDIA4 did the same. In the high fat diet model the silenced animals lost body weight, liver weight, liver fat and triglyceride, and showed liver lesions, so removing the factor made the tissue worse rather than better. Macrophage invasion, lysyl oxidase activity and collagen deposition all rose in the silenced liver in both models. The human material followed the same direction: TCF19 was lower in fibrotic than in non-fibrotic liver, with 15 fibrotic and 17 non-fibrotic samples compared, and staining of a patient cohort of 9 healthy controls, 20 with steatosis and 20 with steatohepatitis put TCF19 up in steatosis and sharply down in steatohepatitis. The paper reports no percentage knockdown for the oligonucleotide.