High-fat high-sucrose diet feeding exacerbates early and complete weaning-induced steatohepatitis with ER stress-related and epigenetic changes at the Cidec regulatory region.

OBJECTIVES

Early and complete weaning has been shown to induce steatohepatitis in mice fed a standard diet (Adachi et al., Am J Physiol Endocrinol Metab. 2025;329:E455-E462). However, whether subsequent high-fat high-sucrose (HF/HS) diet intake exacerbates this pathology, and how endoplasmic reticulum (ER) stress-related transcription factors and epigenetic regulation contribute to this process remain unclear.

METHODS

Male mice were weaned at 17 or 21 days of age, maintained on a control diet till postnatal day 32, and subsequently fed either a control diet or HF/HS diet till 32 weeks of age. Hepatic steatosis and inflammation were histologically evaluated. qRT-PCR and ChIP assays were performed to assess lipid droplet-related gene expression, and CHOP/ATF4 binding and histone modifications in the Cidec gene regulatory region, respectively.

RESULTS

Early and complete weaning increased the abundance of enlarged hepatic lipid droplets and upregulated the expression of Cidec and Plin4, which were further enhanced by HF/HS diet feeding. In the early-weaned HF/HS diet group, CHOP and ATF4 recruitment and activating of histone modifications (H3 acetylation and H3K4 trimethylation) were elevated in the Cidec gene regulatory region.

CONCLUSIONS

Early and complete weaning followed by HF/HS diet exacerbated the development of steatohepatitis, associated with ER stress-related transcription factors and epigenetic changes in the Cidec gene. These findings support the concept that early-life nutritional environments prime susceptibility to steatohepatitis, which is subsequently exacerbated by HF/HS diet.