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.